From the JAMA Network, this is JAMA Author Interviews, conversations with authors exploring the latest clinical research, reviews, and opinion featured in JAMA.
Dr. Preeti Malani (00:18):
Hello and welcome to this JAMA Author Interview. I'm Dr. Preeti Malani, Associate Editor at JAMA and an infectious disease physician at the University of Michigan. Today, I'm joined by two colleagues from Emory University, Dr. Jeanette Guarner from the Department of Pathology and Laboratory Medicine and Dr. Carlos del Rio from the Department of Internal Medicine and the Division of Infectious Diseases. The three of us wrote a viewpoint in early June titled Monkeypox in 2022-What Clinicians Need to Know. It was published online June 13th. Jeanette and Carlos, welcome.
Dr. Carlos del Rio (00:56):
Dr. Jeanette Guarner (00:57):
So monkeypox has been around for decades. The virus was first isolated in 1959 from monkeys in Copenhagen. The first known human case was recorded in 1970 in the Democratic Republic of the Congo. And prior to the spring, imported cases outside of the continent of Africa were rarely observed. But this year we're seeing a growing global epidemic. When the viewpoint was written in early June, there were just over 1300 confirmed cases globally and 45 cases in the US. When I checked earlier today, there are now nearly 800 US cases and more than 8,000 global cases, and obviously those numbers lag and not all cases are identified.
A couple of things are notable about the epidemiology of the current outbreak. The majority of reported cases have no travel related link to an endemic country. And most cases have been among people who identify as men that have sex with men. While monkeypox is not a sexually transmitted infection in the typical sense, it can be easily transmitted during intimate contact. So I want to begin our conversation today with the importance of clinical recognition, which includes awareness, both for patients and clinicians, and the basics of a thorough history and physical exam. Carlos, I note on the CDC website that Georgia has 30 reported cases. I imagine that several of these are in Atlanta. Tell me what you and other clinicians are seeing on the front line and what type of questions you're asking in clinic and what type of advice you're giving patients regarding prevention.
I think the first thing we need to say is that this is a good example of why we should pay attention to diseases that are neglected and that occur in other places and not ignore them. This disease has been going on for a long time in Africa. Jeanette can talk a little more about the outbreak that we had of monkeypox in the United States prior to this one. But in fact, we haven't paid attention to diseases like monkeypox. And right now we're really playing catch up. As you said, the numbers are exploding very rapidly globally and in the United States.
What I hear from clinicians that have seen these patients is that the presentation is very variable. Some patients present with fever, lymphadenopathy is very prominent, the skin lesions are very characteristic, and some of them started with macules, but then go on to develop vesicles. They're incredibly painful. And in fact, one of the most common symptoms that we see is pain. And many of these patients are presented with genital pain, with rectal pain, and with a lot of pain symptoms. And I think that's a very important characteristic.
As far as the history, you need to think about the history of any sexually transmitted disease. While at some point in time travel was important, the reality right now is that we have local transmission. And the most important thing is asking people about anonymous partners, asking people about sexual partners found through dating apps. Many of those patients that we're seeing with infection are either persons living with HIV or people who are taking preps or at risk of HIV. So think about it as you would do with somebody who presents with syphilis or with gonorrhea.
So I'd like to shift to the importance of testing. And Jeanette, this is your area of expertise. If I see a patient later this week and I'm concerned about monkeypox, what do I do? What tests do I need? And where can these tests get done?
Currently, the tests that are being performed are performed usually by the state health departments. There are a few commercial labs that have already developed the test, and we call them laboratory developed tests, that you can send those tests to. So what do we usually receive? We want to receive a swab from the patient, from the lesion. Now we've had one case where they swabbed a macule and that was negative, but then the patient present with a vesicle and then the vesicle was positive. So even the timing is important as to whether you're going to end up with a positive or a negative result.
So vigorously swabbing the lesions, preferably in the vesicle, pustule, or crust state is the best time to be getting this positive results. This samples need to be sent to the state or to one of these labs like Labcorp. There's also Mayo Clinic and ARUP that are working on their tests to be ready. And so that's what you would need to do for this particular testing. If you send it to the state, the state usually does the screening for orthopoxviruses, and then any positive result is sent to the CDC where they sequence the virus, and that gives you the clade.
Jeanette, can you explain what a clade is?
A clade is equivalent to a strain in a bacteria, where you have different variations, even though it's the same bacteria, there's different variations in the different genomic composition. So there's clades in viruses, and then there's the strains in bacteria, but it's the same virus or bacteria that is just a little different. It's a little like the variants for COVID where you have the Delta variant and the Omicron variant. It's sort of similar to that. Whether it's a clade that is associated with the Congo Basin or Central African clade, which is much more transmissible and the virus causes less immunity in the patients and so they end up having more florid disease. Or if it's a West Africa clade, in which case, then it is a virus that is less transmissible. We call the Central African clade Class A versus Class B, which is the West African clade. And that is important for what to do with waste in the lab.
Yeah, this is really helpful. And clearly testing is complicated right now. It requires a send out and it makes me really reflect on what's happened with testing around COVID. And we've spent two and a half years talking about SARS-CoV-2. I think back to the early days where you actually couldn't get a test, unless you were very, very sick and in the hospital. And it took several days sometimes to make a diagnosis. So Jeanette, from a laboratory medicine standpoint, I mean, we've seen what can be done around COVID where we now have highly reliable, easy to use home tests. What do you think is possible for monkeypox testing and are we likely to see more point of care or even home tests in the future?
That is an excellent question, it's interesting that the same instrument that we have currently, that we use for COVID testing, can be used for monkeypox testing. There is the possibility that several of these companies that already do the COVID testing can produce materials and reagents and cassettes that we could use in the same instruments to do the testing, and it would be relatively rapid. It's a PCR, and it is a very rapid test because in two hours you have a result. It would be a game changer if we could have a result that fast.
I would add to that we really are way far behind in rapid testing, in home testing for most sexually transmitted infections. We don't have anything similar to this for syphilis, for gonorrhea, for so many other diseases. So I think there's just also a call to think about investing in laboratory diagnostics to really provide more home testing. We know how home testing has been incredibly helpful in COVID. We need to develop more home testing for other diseases, such as monkeypox, for example. And I think there's a big opportunity here for laboratories. I would also like to say as a clinician, that right now the current system is simply not working. People basically have to deal with health departments that many times are acting like gatekeepers to testing. And what we need to do is we need to do more testing. Everybody knows that if we did more testing, we will find more cases. Number of cases we have is probably a gross under reporting.
One of the things that we need to be thinking about is changing classification, because currently, if it's a West African clade, it is considered a Class B. However, if it's a Central African clade, it is a considered a Class A, and being at Class A makes it much more harder to manage all the material in the laboratories.
Sometimes skin biopsy ends up being done. What's characteristic in terms of the pathology of monkeypox on a skin biopsy?
There's very little written on this. There's a few cases that were studied using skin biopsy during the 2003 outbreak. And then there's a report also of two patients that were studied in the UK using skin biopsies. The pathology is quite similar to what was found in smallpox, but less florid in some ways. So you will have changes that are related to the edema, to having the formation of the vesicle, which is basically [inaudible 00:09:40]. There's a lot of necrosis of the epidermal cells.
And then in the epidermal cells, some of them form multinucleated giant cells, but they're not the typical multinucleated giant cells that you see in herpes, where you have the molding and the margination of the chromatin. Here, the nuclei of the cells look relatively normal, but what you find, the cytoplasmic inclusions, the cytoplasmic inclusions are usually eosinophilic and they can be very similar to a paraphenylene granule, but they are much more abundant. And they're found in this multinucleated giant cells. Some people call this inclusions Guarnieri-like because Guarnieri is the name of the inclusion that was given to the smallpox inclusion. And then you're obviously going to find a lot of inflammation. And interestingly enough, a lot of the inflammation includes eosinophils both in the dermis and in epidermis.
So Carlos, coming back to the clinical picture, you mentioned some of the presenting symptoms, especially lymphadenopathy and pain. What else is in the differential diagnosis?
Well, in differential diagnosis we see herpes infections, we see chickenpox, we see syphilis. In fact, the descriptions that we have from colleagues in the UK, for example, is about 30 to 40%, one in four, one in three of these patients, have an associated STD. So don't think about monkeypox by itself. Think about they may have co-infection with herpes, with syphilis, or other sexually transmitted pathogens.
Tell me about antivirals. What do we know and how might these be used?
Most patients will just require symptomatic treatment. And I think it's really important to think about treatment management of pain. Pain becomes the most important symptom in most of the patients. A lot of discomfort, many complain of proctitis and very severe proctitis. Now, if you have immunocompromised individuals, if you have persons living with HIV, if you have people with lymphomas, with malignancies, with hematological malignancies or transplant patients, or you have, for example, pregnant people or people under the age of eight, it is important to consider the use of antivirals. And among the antivirals we have, for example, the one being talked about the most is tecovirimat. Tecovirimat is an antiviral that was approved by the Food and Drug Administration for the treatment of smallpox in adults and children. We have no data about its effectiveness to treat monkeypox, but animal studies suggest that it is effective to treat other orthopoxviruses. And as Jeannette said, monkeypox is very similar to smallpox.
We know from clinical trials that this drug is safe, with very minor side effects, but because it's not approved for the treatment of monkeypox, the CDC currently holds an expanded access protocols, what sometimes is called a compassionate use protocols, that allows it to be used in the treatment of monkeypox. The problem is that you, as a clinician, if you decide you want to treat somebody, you then need to talk to CDC, you then need to go through this process of compassionate use. What I've heard from many people is, for example, hospitals are saying, "Well, we need to also review the protocol because it's an experimental therapy," and that delays the access to therapy. I heard somebody over this past weekend diagnosed with monkeypox on a Friday, and it wasn't until today that they were able to get the drug and treat the individual, because over the weekend, there was no way of getting this approved. So a lot of barriers to getting this drug and to be able to use it.
There's also a vaccine immunoglobulin that has been tested, as well as Cidofovir that has been recommended as a potential drug to be used. Cidofovir is a drug that was approved for the treatment of cytomegalovirus retinitis in persons with AIDS. And again, we don't have data available on its effectiveness with monkeypox. However, people say it may be effective. The problem is Cidofovir is fairly toxic, and I think that you would rather use tecovirimat as an initial therapy. As far as vaccination is concerned, there's basically two vaccines available. One is what's called the Jynneos vaccine and the other one is ACAM2000 vaccine. They're two different vaccines.
The Jynneos vaccine is a vaccine that contains a live virus that does not replicate effectively. It's administered as two subcutaneous doses, four weeks apart and is licensed by the FDA for the prevention of smallpox and monkeypox for persons ages 18 and older. It's effectiveness is supported by animal studies. In contrast to that, the ACAM2000 vaccine is a vaccine that contains a live vaccinia replication-competent virus. It's advantage is that it's administered as a one dose with a bifurcated needle, very similar to what we do with the smallpox vaccine. Here, the immune response takes about four weeks to develop because you have to have the take very similar to what we had with smallpox. The problem is that it has significant side effects. And again, this vaccine can have pain, swelling, redness, rash. You can have disseminated vaccinia as a result of giving this vaccine, and then occasionally other conditions such as myocardial infractions, myocarditis, and other conditions have been seen with the vaccine. So it is not a vaccine also you would administer to pregnant individuals.
So the ideal vaccine to use is the Jynneos vaccine. The problem is that there's a very limited supply right now in our country of this vaccine. So prioritization of the vaccination is going to be very important. If we had enough vaccine, you could start vaccinating, and many places would like to do that right away, because you can not only vaccinate people for prevention, but you can vaccinate people post exposure. If you have been in contact with somebody with monkeypox within the past four to 14 days, you could go ahead and rapidly vaccinate individuals. And if not prevent the disease, at least make it significantly less severe. So we have problems right now with access. We have problems with access to testing, access to therapy, access to vaccine. And again, really, we need to be moving a lot faster than we are in order to satisfy the clinical demand that is rapidly growing.
Your comments really resonate with me because, again, we're at well-resourced tertiary care health systems, but these medications and vaccines are not sitting in the hospital pharmacy waiting to be ordered. And the process, that idea that on Friday evening, you make a diagnosis and it's just very difficult to access the therapies that are needed. I hope some of that changes in the coming weeks. It sounds like, at least with the vaccine rollout, there is some reason for hope, but the portion of people at risk versus the number of vaccine doses, it's a mismatch.
It's woefully inadequate. And again, in several months we'll have enough vaccine, but can we wait several months the way these numbers are growing of infection? And my fear is that by the time we have enough vaccine, there's also going to be a disease that is going to be out in the population, and we're not going to be able to contain this outbreak.
My last thought, Carlos, I feel like we should spend a little time reflecting on this. We're dealing with a vulnerable population, and basic access to care isn't always there. I know you've worked a lot in this space. Tell me what we can be doing to encourage people to seek care. What is being done on the ground level, from advocacy groups and others in the community? And again, we're talking about a particular population that appears to be at risk right now, epidemiologically. But monkeypox can affect all of us. The virus doesn't care.
This is about health equity. And what I worry about, for example, with limited access to vaccine, is that wealthy, middle class, white individuals are going to get vaccinated and African American, Hispanic individuals are not. So I think we need to keep a focus on equity as we roll out these vaccines, as we do testing, as we do therapy, as we do outreach. We know from the world of HIV, that working with community is very important and having the community organizations really involved at the roots level to really improve access, improve equity, provide information, provide counseling, I think is critically important. So activists are, like they were at the beginning of HIV, are critically important to ensure that we have the access we need. Like we did in the early years of HIV, they pushed the government very hard, but they also got a lot done. And I wish we would see a similar level of activity right now from activists to get more vaccine, to get more therapy, to get more testing. So one thing that I think is missing is activism.
I hope that some of that grassroots activism is there and that we will be in a better place in the coming months, and that those case numbers are not going to continue to skyrocket. Doctors Guarner and del Rio, thank you as always.
It's been a pleasure to be in a podcast with you.
This episode was produced by Shelly Steffens at the JAMA Network. The audio team here also includes Jesse McQuarters, Daniel Morrow, Lisa Hardin, Audrey Forman, and Mary Lynn Ferkaluk. Dr. Robert Golub is the JAMA Executive Deputy Editor. To follow this and other JAMA Network podcasts, please visit us online at jamanetworkaudio.com. Thanks for listening!