Updates from the COVID-19 Registry: Interview With Dr Freeman

Dr Freeman is an assistant professor of dermatology, director of Global Health Dermatology at Massachusetts General Hospital and Harvard Medical School, and a member of the AAD Ad Hoc Taskforce for COVID-19.

Dr Green is the section editor of The Dermatologist’s Psoriasis Center of Excellence, clinical professor of dermatology at George Washington University School of Medicine in Washington, DC, and on the National Psoriasis Foundation Medical Board.

Transcript

Dr Larry Green: Hi, everyone. Welcome to another really informative podcast. My name’s Larry Green. I’m section editor of the Dermatologist Psoriasis Center of Excellence and clinical professor of dermatology at George Washington University School of Medicine in Washington, DC.

Today, we will be discussing the data coming out of an international registry created in collaboration with the International League of Dermatological Societies and the American Academy of Dermatology with Dr Esther Freeman who is the principal investigator and director.

Dr Freeman is a member of the AAD ad hoc taskforce for COVID-19, a very active member, and director of Global Health Dermatology at Massachusetts General Hospital at Harvard Medical School in Boston.

She’s been very, very much a part and a leader in our learning about COVID-19 and dermatologic manifestations. She is in charge, director of the COVID-19 registry for the American Academy of Dermatology. Dr Freeman, Esther, thanks for joining us.

Dr Esther Freeman: It’s a pleasure to be here today. Thanks for having me.

Dr Green: It’s an honor. There’s so much going on during this pandemic. You’ve been at the forefront of leading us dermatologists and telling us what we need to know, teaching us about dermatologic manifestations of COVID-19. Let me ask you, based on the data that you’ve been able to analyze so far, tell me a bit about the spectrum of cutaneous findings that we have associated with COVID-19.

Dr Freeman: Absolutely. I have to say that even having cutaneous manifestations of COVID-19 was a little bit of a surprise for us at the beginning. If you remember earlier reports coming out when we first started hearing about the virus early on in China, we didn’t hear a lot of reports about skin findings in COVID-19.

It was only as we started to hear reports a little bit maybe coming from China and Asia, but then as we started hearing reports from Europe, here and there we heard about one or two cases with skin findings. This was the time that I had proposed to the AAD that we would launch a registry to collect what was happening to our skin patients overall with COVID-19.

At the time we started thinking about the registry, there weren’t any skin manifestations. As we started to hear about this, I thought, “You know, let’s program it just in case [laughs] to collect skin manifestations.” I didn’t realize that 98% of what we were going to collect was skin manifestations. It went very quickly.

As you mentioned, things were changing so rapidly that literally in the beginning we were reprogramming the database every six hours. We would hear something new and we’d reprogram the database to capture it. It was changing so, so quickly. I’d say the first surprise was at the beginning we didn’t even think there necessarily were going to be a lot of skin manifestations. Then very quickly we started hearing about these.

It’s also interesting in the perspective of how we’re learning about medicine in these days is we weren’t hearing about it in journals. We were hearing about it through social media and through lay reports. That’s how we were getting the first news. I was like, “We really need to characterize that in a more systematic way.”

In terms of where we are right now with the registry, we’re at over 1,000 cases from 41 different countries. What’s a real testament to the international collaboration and the whole world coming together is not just the number of cases we have from healthcare providers around the globe but in how quickly we were able to launch this on a global scale.

From when we first proposed the registry to the AAD taskforce and to the International League of Derm Societies to going live and collecting our first case and going through ethics review was just nine days. That included programming the entire registry, going through the ethics process, and building an international collaboration, and collecting our first data. It was very rapid.

To me, that’s a real testament to everyone coming together and being willing to collaborate, people that had never met before and were suddenly thrust together to try to make this work. That, to me, has been my COVID silver lining.

Dr Green: It’s amazing, Esther, how quickly that came together. I know you published a lot in the GEN lately but specifically about the collaboration, harmonization internationally across the COVID-19 registries. It is amazing how quickly you’ve been able to accomplish this and work with dermatologists around the globe.

Dr Freeman: One thing that was nice, because I work primarily in global health dermatology, I do spend a lot of time with folks in different countries. A lot of those bridges were somewhat already built. I will say everyone was so open and willing to collaborate, not just in dermatology.

For example, the Global Rheumatology Alliance was about 10 days ahead of us in terms of launching their international registry. They were incredible. We reached out to them. They shared some of their tips of how they navigated the IRB and ethics process.

All of these barriers and silos that exist normally, temporarily disappeared. People were really willing to work together, which was, for me, really critical at that time.

Dr Green: I don’t know where to start. Let’s start talking about some of the cutaneous manifestations that have been noticed in the registry starting from the most common to the least common. Then, we can talk about some of the challenges you have confirming this both nationally and internationally.

Dr Freeman: Absolutely. If you look at the registry overall, as I said, we’re at over 1,000 cases from 41 countries. About half of those cases have been entered by dermatologists. The other half by, for example, primary care doctors, emergency room physicians, and ICU, things like that. This is not a patient-facing registry.

What I mean by that is patients can’t enter their own data. We made that decision early on. As you know, when you’re talking to your patient and you ask them to describe their rash, they’re like, “I don’t know. It’s like red, itchy bumps.” We wanted to be able to classify these more carefully. If you look at overall, we collect both suspected COVID-19 and confirmed COVID-19 cases.

The reason, particularly for that, is, especially at the beginning of the epidemic, nobody could access a COVID test, though it was a rare person who managed, in the beginning of the epidemic, to get COVID tested in any kind of timely fashion. It was very rare to happen.

If you are a suspected case, we also collect how close a contact. Your parent was COVID-positive, but you never got a test would be one example of someone who’s suspected to have COVID-19 but not confirmed. If you look at everybody both suspected and confirmed, the most commonly reported skin manifestation is pernio or chilblains, which has also been come to known as COVID toes in the lay press.

If you focus down on just the lab-confirmed cases, the number one most commonly reported is a morbilliform rash, which is certainly not that surprising in viruses, that’s a common viral rash, quickly followed by pernio or chilblains. Even in just lab-confirmed, pernio or chilblains is our second most commonly reported.

Then we have other conditions like urticaria, papulosquamous eruptions, some vasculitis, retiform purpura in our very sickest patients. We’ll talk a little bit more about pernio, chilblains, and COVID toes because that’s probably also one of the more surprising findings.

One thing, if you look at the overall spectrum of different cutaneous manifestations, the most interesting finding is the fact that different severities of COVID travel with different skin findings. For example, pernio or chilblains, only 16% of our patients who report having pernio or chilblains with COVID-19 are hospitalized.

They generally do pretty well. They come out of the virus very well. They tend to do well. It seems to travel with less severe disease. On the other end of the spectrum, you have retiform purpura, which would be caused more by microthrombi, by clotting.

On one side, you have inflammation with pernio and chilblains. The other side, you have more of these clotting issues with retiform purpura. In those patients, 100% of them in the registry were hospitalized. You get a sense that there is not one-size-fits-all.

Dr Green: So interesting, especially with the dermatologic manifestations from A to Z. Do you think a lot of these are based on our immunologic reaction to the virus rather than the virus itself? Where do you think that fits in the spectrum?

Dr Freeman: So tricky. I’m glad you asked that question. I would have said, to be honest, earlier on I thought it was all going to be a post-viral inflammatory mediated process. That was my hypothesis in the beginning. What surprised me was one of the articles by Coleman, Nero, et. al in the British Journal of Dermatology where they did skin biopsies on seven kids with pernio or chilblains.

These kids were PCR-nasal-negative and they even swabbed their throats. They were negative in two places. These kids were suspected to have COVID-19. By the time they developed the pernio, basically, the virus had cleared in their nose. On biopsy, they were able to locate SARS-CoV-2 sitting in their toes.

They could even take an electron microscopy picture of this perfect little coronavirus sitting in someone’s toe. I’m still trying to understand. It provided the missing link of, “Is this related to SARS-CoV-2, or is it everyone just randomly wandering around barefoot? No, it’s actually related to SARS-CoV-2.”

It provided that missing link being able to see the virus in their toes. It does beg the question of, how much of this is a direct viral effect versus some sort of triggered inflammation? We’re still parsing that out.

Dr Green: It’s amazing the virus is found that late after they’re no longer, supposedly, infectious or contagious in the respiratory tract and it’s still in the body. There’s talk about chronic COVID infection like chronic lung infection, which is a whole nother issue and that’s not necessarily dermatologic. I’m wondering if that fits in with that, something that time will tell. I don’t know if you have a comment on that.

Dr Freeman: We just did a presentation last week or maybe 10 days ago at the EADV on the concept of long-COVID or long-haulers in dermatology. I would maybe separate that from the concept of chronic COVID. I would say COVID that is lasting beyond the acute period.

When we analyzed dermatologic symptoms of COVID-19 to look at duration, we found just like there’s different severities of COVID-19 with different types of skin rashes, there’s also different durations of these different rashes. For example, urticaria or hives only lasts about five days, which makes sense. We’re used to it coming and going pretty quickly.

Pernio or chilblains, the median duration was around 15 days. We had six patients in the registry where their duration of pernio or chilblains lasted beyond 60 days but becomes into this more long-hauler or long-COVID. In different countries, they call it different things.

In fact, we have some patients who now have had persistent pernio or chilblains lab-confirmed related to COVID-19, we know that they had COVID, that’s lasted longer than 150 days.

Dr Green: You mentioned, by the way, the EADV poster that was just presented. Can you tell me more about that, what the purpose of that is? I’m sure that’s the latest that we have on COVID. That’s the most recent presentation. Can you elaborate on that?

Dr Freeman: Yeah. We did an oral presentation at the EADV on this topic. What we were looking at was, basically, acknowledging the fact that there are COVID long-haulers in dermatology and even in what we would call dermatologic-Driven disease. These were patients that didn’t have a lot of other symptoms besides pernio and maybe some fatigue.

Interestingly, as I said, in these patients with lab-proven disease, some of them have had persistent pernio for many months. It raises more questions than answers. Did this trigger some sort of autoimmune process for them? How did this trigger some sort of chronic inflammation that they’re dealing with? There’s still a lot left to be learned.

There was another interesting presentation in the same fashion, at the EADV looking at the role of interferon and seeing that in different skin biopsies and different skin conditions with COVID-19, there were certainly high levels of interferon.

There’s a signal there and something that we’re going to continue to see. Why exactly it’s happening, we’re still trying to figure out. I’d like to say, it’s like the tip of the iceberg. If we see in the registry there’s a couple patients with this, that means there’s a lot more in the community.

Dr Green: I’m sure it is. It’s only the tip of the iceberg in all we’re learning about COVID. We’re still learning about chronic Lyme and chronic EBV after how many years? I still think it’s impressive how far we’ve come in less than a year with finding out COVID for manifestations and all you’ve learned through the registry and stuff like that.

Pernio is so interesting with COVID-19. Can you tell me a little bit more about pernio infection since it wasn’t so common for us in dermatology? Now, it’s all of a sudden quite the rage.

Dr Freeman: It’s challenging. It makes you wonder. We hadn’t spent a lot of time studying pernio or chilblains before COVID-19. There was some data on it but not a ton. It does make you wonder, is it possible that pernio or chilblains has always been virally-triggered and we just didn’t know it? I don’t think we know the answer to that.

It does raise the question, are some of these patients who were triggered by COVID-19 going to end up with recurrent pernio or chilblains? When we see other patients separate from the COVID pandemic who have pernio or chilblains or who maybe even have recurrent pernio or chilblains over the course of their lives, do we really know?

Could that have been triggered by a virus in the very beginning? We don’t know the answer to those questions. It’s really tricky.

One thing you brought up earlier on was about we mentioned these patients who were found to have SARS-CoV-2 sitting in their toes on biopsy. Is that live virus? Is that dead virus? Is this just virus that’s left over from when they were infected and it’s still some sort of post-viral inflammatory response? This all raises more questions than answers.

Dr Green: Let me switch the topic a little bit and talk about...We have patients on immunomodulating therapy for people taking antibiotics for psoriasis, for atopic dermatitis, and other conditions like that. Do you think there’s any problems with immunomodulating therapy, any aspects of immunomodulation that you want to discuss that you think are applicable with COVID-19 infection?

Dr Freeman: Yeah. This has been tricky from the very beginning. Early on, we were really worried that our patients, for example, on biologics, were going to end up at higher risk for COVID. That was our concern. People were very, very concerned about that.

I have to say, I’ve been reassured by the data that we’ve now seen several studies, both from the rheumatology literature and from the dermatology literature that don’t seem to suggest that our patients with biologics are necessarily getting any more severe COVID than other patients of similar age and profile. I’ll give you one example.

We talked a little bit about our collaboration between different COVID registries. We’ve been collaborating with PsoProtect, which is one of the COVID-19 psoriasis-specific registries. We collaborated with them and pooled some of our data from the AAD and ILDS registry.

This paper was recently published in the Journal of Allergy and Clinical Immunology just in October. It’s titled, “Factors Associated with Adverse COVID-19 Outcomes in Patients with Psoriasis, Insights from a Global Registry-Based Study.” In this study, evaluated 374 clinician-reported patients from 25 different countries. Hospitalization was not more frequent in patients on biologics.

In fact, it was more frequent in patients on other immune modulators and other treatments than biologics. Different biologic classes were not seen to be different. That type of data has been seen in the rheumatology literature as well. I’ve been reassured. That being said, it’s still really tricky to figure out what to do with your individual patient.

My other hat is I’m the chair of the Clinical Guidelines Committee at the AAD. It’s important for people to recognize that when we normally produce guidelines at the AAD, it’s a very evidence-based-Driven process. We spend a lot of time evaluating the literature that’s out there. Very tricky when there’s no real literature to base those guidelines on.

When we produce this interim guidance, I want people to be aware that it’s very different than our much more robust, normal psoriasis guidelines, for example. The National Psoriasis Foundation, the NPF, has done a really nice job with producing some guidance around this. All of these guidelines from all these different groups are interim. We don’t have the data.

It’s a bit tricky when you’re faced with a patient. Certainly, I wouldn’t recommend rushing to take anyone off biologics. I, myself, have had patients where now we are in the middle, we’re month-nine of COVID, and I want to start them on a biologic. That’s tricky.

You have to have an individual-level discussion with your patient about their risks and benefits. As much as possible, explain to them what we do know, what we don’t know in terms of biologics and COVID-19.

Dr Green: I agree. That’s makes the most sense. You still have the chronic disease state like atopic dermatitis or psoriasis. Having that and what COVID could do when you’re chronically inflamed and untreated versus treated, that’s a discussion, like you said, you have to have with the patient. Time will tell.

Eventually, we’ll see once we get patients who take biologics and then, unfortunately, do come down with COVID-19 to see how they respond long-term. Will then have chronic COVID? Will they have long-COVID infection? How many of them do? How many of them don’t? We don’t know. You talked about evidence. We don’t have evidence. It’s early on.

Dr Freeman: We have evidence for the short term. We know, at least, you’re not more likely to end up in the hospital, which is good. You’re absolutely right, we don’t know what this means for you necessarily six months after you’ve gotten COVID.

Like you said, there’s so many different pieces of it. If you have someone who’s in such a horrible psoriasis flare that they’re going to become erythrodermic and end up in the emergency department, that’s not good. [laughs] It’s this balance of risk and benefits.

Dr Green: Right. No one wants to go to a hospital overrun with COVID because you have a flare of psoriasis. We started talking about research and where we need to go. Where do you think additional research is needed to help us understand COVID-19 manifestations for the skin?

Dr Freeman: I think a few things. One is, I certainly think more perspective data is needed. One limitation to the registry is that you have to think of the registry as a giant case series. We don’t have a denominator. I can’t tell you of everyone that gets COVID, what percentage is going to end up having a skin manifestation. You can’t tell that from the registry.

We don’t know what our population base is. One thing is that as we get these larger COVID cohorts that are not derm-related to try to understand a little bit more accurate a sense of what percentage of patients with COVID do get these different skin manifestations. I should point out that the numbers vary wildly right now country to country.

It’s possible that there’s some geographic and genetic differences in how that manifests. There may be a reason that we’re seeing a lot of wildly different numbers. The other thing, to me, that’s really tricky is understanding underlying pathophysiology.

I’d like to understand, for example, with these long-COVID or long-haulers, what is Driving this persistent inflammation? What is the role of interferon? These are some questions that are lingering for me on the more pathophysiologic part.

Then we’re also starting to collaborate with the NIH to look at some of the genetics around this. Are there certain genetic polymorphisms that might trigger a certain type of COVID or certain type of skin manifestations in some patients and not others?

I feel like every day there’s more questions to explore. I keep thinking that, it’ll be a little bit more clear to me in a month or two months, we’ll have this all figured out. In two months, I have 50 more questions than I did two months ago. [laughs]

Dr Green: Classic example of the more you know the more you don’t know.

Dr Freeman: That’s exactly right.

Dr Green: I hope we keep finding out more and more and we get to the point where there’s less we don’t know. I appreciate all your efforts and everything you’re doing that’s made a huge difference to us as dermatologists. Is there anything else you want to add or anything that we’re missing when you talk about COVID-19 for us dermatologists?

Dr Freeman: Absolutely. One other piece that people often ask me is about COVID testing and timing of testing. We did publish a paper on this looking at timing of PCR and antibody testing, specifically in our dermatology patients. One thing that’s super tricky, especially when it comes to pernio or chilblains, is that the timing of the testing really matters.

It seems like with our pernio or chilblains patients, they are often getting pernio or chilblains one to four weeks after COVID-19 infection. They may be out of their PCR-positive window at that time, which is good. They’re no longer infectious. We like that. We know that 15% of our patients that are entered in the registry with pernio or chilblains are still PCR-positive.

I still do encourage people to PCR test if you have a patient who comes in with pernio or chilblains and they don’t have another good reason. If they were walking barefoot in the snow, then they probably have another good reason.

One of my patients got a new pair of golf shoes and was convinced that his toe blister was COVID. I was like, “No. It’s your new golf shoes.” You have to have a little bit of common sense there. If you have a patient who’s coming in, they have no other reason and they’ve developed the COVID toes, or the pernio, or chilblains recently, it’s totally worth testing them.

The public health impact of missing an active infection is so high. You don’t want them to transmit that to someone in their family who’s going to end up in the hospital, even if they, themselves, are going to do fine. To me, it’s still worth COVID testing them even though you know, probably, there’s about an 85% chance they’ll be negative.

You don’t want to miss those few cases that are potentially still infectious. That’s point A. Point B is that there are some patients, it’s super tricky to prove they have COVID. I would follow that up with, does it matter? If they are out of their PCR-positive window, we know that patients with mild COVID may only develop a very tiny antibody response.

It may not even be an antibody response that’s detected by commercial tests. A lot of these patients are developing an IgA antibody response, which is not detected on commercial tests, which are IgM or IgG. They might have it for a hot minute. It may be that their response is primarily T-cell-Driven.

You may have a patient who’s PCR testing negative because they got their toes after their acute infection. They may never test antibody-positive on commercially available assays. It’s important to inform your patient, “You know what, you may still have had COVID and you should still protect yourself and wear a mask.”

It also brings me to the point of, does it matter if we can’t prove that? [laughs] I would say when you’re faced with a negative PCR and a negative antibody test, keep in mind that does not mean the patient did not have COVID.

Dr Green: Very important. That’s someone still, that maybe the registry would like to know about even though they’re PCR-negative. We want to account for everything.

Dr Freeman: Absolutely. If you have a patient where you are suspecting that this is COVID-19 and they have what’s a suspected dermatologic manifestation, please, do enter it in the registry. We allow you to tell us how suspicious you are.

You get to say, “I really think this is COVID but I have these lab tests and they were all negative,” or you get to say, “You know, I’m not really sure if this was COVID but I’m putting it in here as a possibility.” We take that into account when we do the analysis. Then the last thing I’ll say...I keep saying the last thing. [laughs]

Dr Green: It’s all great. Good information.

Dr Freeman: Forever. The registry is still live. We would appreciate, please, continue to add your cases. The story is far from over. We’re continuing to learn a lot about these patients. There continue to be new manifestations or different timing, different test results. Please, do continue to add your patients. It’s very helpful for us.

Encourage your colleagues who are not in dermatology also to enter them. We have recently launched, very quietly, the ability to do data requests from the registry. We are now opening ourselves up and you can create a scientific proposal or an application. It will be reviewed by our data governance workgroup for the registry. You have to have a specific research question.

We’ll evaluate your research question and then we can grant you access to specific data from the registry to answer your research question. The idea is this is meant for everyone. This is everyone’s data. It doesn’t belong to any one person.

Dr Green: Thanks. That’s great for all of us who are interested, and anyone who’s interested, especially, in a specific avenue looking into more details. Thanks, Esther, for all you’ve done and all you’re doing. We appreciate it. Hopefully, we’ll all get through this pandemic together without all getting COVID. Long before that, we hope.

Dr Freeman: Stay safe. Stay healthy.

Dr Green: Thanks. You, too. Thanks for your time. Thanks, everyone. Please, don’t forget to put any comments you have in the comment box. We hope you enjoyed this podcast.