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MAY 18, 2020 -- HIV clinical fellows Eric Meyerowitz, MD, from Massachusetts General Hospital and Aaron Richterman, MD, MPH, from Brigham and Women's Hospital, collaborate on a biweekly deep dive into the COVID-19 literature. Medscape interviewed the pair to find out how they choose what to include, what they think of the quality of the science, and what they find most intriguing about SARS-CoV2.
This interview has been edited for length and clarity.
How did you decide to start doing this?
Aaron Richterman, MD, MPH: In early January, Eric texted me when there was a news article about this cluster of pneumonias in Wuhan to say this looks scary. I think he put "SARS?". Eric and I are friends from medical school who through happenstance ended up as HIV fellows across town from each other.
Since then we've been following very closely. In February, I was In Haiti and this was when things were really heating up in China, and everyone was concerned that it was going to be more widespread. I was thinking, "Could this make its way to Haiti?" That seemed like a crazy thing to think about then.
By the time I got back to Boston, it was clear that this was not going to be contained. Within the Division of Infectious Diseases at the Brigham, all our routine activities were pushed aside. Everyone was in rapid preparation mode, and this was before we had any cases in the area. As part of our HIV fellowship year, we organize conferences and educational activities, so our clinical directors asked us to put together a presentation to summarize what was known at that point for our Harvard-wide ID conference.
Eric Meyerowitz, MD: There was a moment, I think this was when Aaron was still in Haiti, and we were basically following this on Twitter and seeing it go from China to Iran and Italy, and then hearing about the start of cases in the US and feeling like, you're watching this in slow motion.
How did you approach the first presentation? Was it decided from the get-go, that you'd work together?
Richterman: I think the same email was sent to both of us asking us to put the first one together. I think we were asked because this was a new virus and we had a lot of background in HIV.
We spent a week or two on the first presentation. It was early enough where you could read everything, and we went through everything in detail. There was so much dogma and rumor, and this and that coming out. We tried to find the evidence where it existed. One of the silver linings of this whole thing has been the amount of solidarity that is felt through the scientific and clinical community.
We wanted to share this with as many people as would be interested. I was thinking about colleagues in Haiti and elsewhere. We publicized it, not really knowing what would happen, and then we got feedback from people all over the world who found it to be very helpful.
And it was also very helpful to us in anticipation of our own clinical duties. So then we thought maybe we should make this a regular thing.
Meyerowitz: New York was obviously hit a week or two before we were hit, so we knew what was coming, and we were fortunately able to review just about everything out there the first time.
What's been really exciting is how much has been learned over the last 8 weeks. As soon as we did the first presentation, there was already a lot of new stuff. Pretty much the next day, we started making a new slide set to catalog all of the changes.
You mentioned that you could read everything for the first one, but since then, the publications have exponentially increased. How do you decide what makes the cut?
Richterman: It's kind of an easy process. After we do the presentation, there's a bit of diastole for a couple days. We keep on top of everything that's published in the major journals: Science, Nature, New England Journal of Medicine, Lancet, JAMA. Then over the course of the first 4 or 5 days as we're finding new papers, Eric and I are literally texting each other: Is this something new? Does this matter to something clinically that we're doing? Does this add some element about the biology or the epidemiology of the virus?
Within about a week we start to formulate the theme. We're trying to highlight new aspects, or new angles to what's being understood, and then doing deep dives within those.
There are experts in every corner of this, from the basic biology, to clinical experts, clinical trials experts, epidemiologists, and modelers. We try to identify who the experts are and read everything they put out. We watch closely on Twitter. We look at the preprints and the discussion about the preprints. We don't pretend to understand everything or to be experts in one way or the other, but we try to sit within the uncertainty knowing that 2 weeks later, we can revisit something and say, Here's some additional evidence pointing us one way or the other.
A concrete example is the question of viral load in the nasopharynx and when does it peak? Does viral load correlate with anything? There are papers that say that it correlates with severity or others that say it doesn't. We try not to say things forcefully, we try to come back to something later on and say, "Look, there is conflicting information and we just don't understand it at this point."
How do you decide who focuses on what papers?
Meyerowitz: It comes naturally. Aaron has an MPH and an amazing public health mind, so he will often view the complex modeling studies and the studies about viral shedding and other things that have a lot of policy implications.
I am very interested in therapeutics. Early on, one of the scary things was that there were no treatments. I'm interested in a lot of the virology.
Other things, we just split up. The nice thing is that we go through it a couple of times, so we're teaching each other throughout, and even if I present something it could be from a paper that Aaron found or vice versa.
Richterman: We go through everything together, and we present to each other and we challenge each other: Is that really what it means? We're fortunate to be around a lot of very smart people in these areas and being part of conversations with our mentors where we can ask them what the implications are.
Early on, Eric was very involved with helping the team with the clinical treatment guidelines at MGH [Massachusetts General Hospital], so he ended up reviewing a lot of that therapeutic data, which as, you know, had a lot of gaps.
How much time do you spend on this?
Meyerowitz: I think probably each presentation takes 80 to 100 hours from finding the papers, reading the papers, digesting the papers, making slides, talking it over. We usually practice it once or twice, but I think that's fair, would you say so, Aaron?
Richterman: That feels like a lot, but maybe. For better or worse, this is the job right now. I mean, everything is basically around COVID-19. All of my other work is basically on hold, all my clinical work is focused on this. All of my nonclinical work is focused on this.
In some ways we get to double-dip because we're reading papers that are also helpful for the other things that you're doing. It certainly doesn't feel like it's a separate project. This is what everybody's working on right now within the Division of Infectious Diseases at both of our hospitals. Reading papers and staying up to date is something that everyone is trying to do. We're maybe trying to do it in a bit more detail and with a bit more structure.
In going through the data, what do you think of the quality of the science?
Meyerowitz: Overall, it's really remarkable. I think there is a ton of really high-quality science being done. One of the exciting things now, as we do these, is to see the quality of the studies getting better. There are now a number of pretty excellent treatment trials, and obviously when we were preparing the first presentation a few weeks ago that was not at all the case.
I'm really blown away by how much good work is being done. Seeing the collaborations across institutions and across countries is incredibly inspiring. In that same spirit, it was Aaron's idea to basically put this up on Twitter as a resource. All of these groups are collaborating, and that's going to be so important for us to get through this.
Richterman: I would just add that there's obviously the full spectrum of quality. It is really remarkable. Take the lopinavir ritonavir randomized study, the speed with which that was put together—a really high-quality randomized controlled trial—in the middle of a brand-new emergency. They enrolled patients in 2 weeks. From the beginning, we had the report of the first 425 patients in the New England Journal that really informed the dynamics of this infection, the identification of the pathogen within a very short period time. I think all of that is unprecedented.
Meyerowitz: Those very early studies, the clinical epidemiology studies from The Lancet, and from the New England Journal, even from February, a lot of their findings have held true. The risk factors that they were able to identify are a lot of the same risk factors that have borne out again and again in multiple studies across continents. Because of all that work, we were way ahead of where they were when this all started last fall.
Richterman: I think the area where we most want data, but also by the nature of the data that's available, that has had the most limitations is in therapeutics. Early on everybody was really grasping for any sort of evidence that something that might be helpful in a disease that had no treatment. And often it was these observational studies that were uncontrolled and had a risk of bias, but people were grasping at straws at that point.
Are you a fan of preprints?
Richterman: It's interesting seeing some of the studies that we looked at as preprints get published a month or two later. And seeing that process of refinement. We always try to take a skeptical eye because these are not peer-reviewed. If it's not in an area that we feel that we have a particular expertise, we try to be very cautious. A lot of times we'll read preprints and think, this is really interesting, but we cannot include this right now because we don't feel it passes scientific muster.
It's probably a net positive because a lot of the insights that we have into the behavior of this disease came out of preprints. There was the Wölfel paper in Nature of the nine German patients—that started as a preprint. That was very important for understanding the basics of the viral dynamics, and I think that we benefited greatly from that, whereas with others, it's harder to say.
Meyerowitz: I completely agree. It's one of the reasons we always make sure that it's clear when we are going to talk about something that's a preprint because certainly it's always better to have a peer-reviewed source. But given the pace of everything, it really has been helpful in some circumstances to be able to point to other data too.
You've had to reference press releases a few times. Is that something you ever thought you'd be doing?
Meyerowitz: No, no. In the last video that we did, we spent a lot of time going through the treatment updates with the remdesivir updates and the IL-6 [interleukin-6] updates with tocilizumab and sarilumab, and we talked about what was appropriate to include. We ended up wanting to discuss those because there were such big decisions being made off that information. It was helpful for us to go through and understand what details were actually known. Whether it was specific data from the press release from the NIH [National Institutes of Health] about remdesivir or the specifics in the press releases of either the French tocilizumab study or the industry-sponsored sarilumab trials because those are things, certainly at our hospitals and I think far beyond that, that are having an impact immediately.
I hope we don't have to do that again because it's uncomfortable. We're trained, I think, appropriately, on how to read a paper and the things that we're supposed to look for—looking closely through the different tables. It makes us uncomfortable to draw conclusions off anything less than that. Even early on, obviously, in the first update, we wanted to give some treatment updates, but there were no good treatment trials. At that point, we were talking about preprints and nonrandomized trials because that was what was having an impact at that moment. That's how we try to balance it.
Richterman: Yeah, we're not trying to draw any conclusions. We try to really point out where the uncertainties remain. I don't want to point to any specific studies, but a lot of the press releases are conflicting and they don't make a lot of sense sometimes. And we try to just point out what has at least been released.
From a virology point of view, what's the most intriguing thing so far about this virus?
Meyerowitz: We spent a lot of time going through cell entry data. Very early on the focus was almost exclusively on the ACE2 [angiotensin-converting enzyme 2] receptor and is ACE2 the answer for everything—Is it the cause of the difference in outcomes based on age? It's been very exciting to see the work that's been done about other potential mechanisms for cellular entry.
Then I think the questions of shedding—what does shedding represent in terms of infectious virus, what is just viral RNA? The question of viremia that we started to address in update part 4 has been incredibly interesting.
Aaron and I have talked about trying not to make comparisons to other viruses or other processes because this is a completely new disease. Just because you know something was true for influenza or for some other virus, you can't make those same assumptions here. Even things that you know about SARS-CoV, for example, the potential entry into T lymphocytes being much more easy with SARS-CoV2 compared to SARS-CoV. It's humbling, but it drives the point home again that until you know something, you can't say that you know something. You really have to wait for the science to be done, for the good high-quality studies to prove each step of the way because it's a completely new virus.
Richterman: I don't know if it's the virology, but I find the interactions with our immune system very interesting. There are some interesting hypotheses around cellular immunity and the development of neutralizing antibodies, and a major unanswered question is why there's such a wide spectrum of disease. I don't think we know and it's an important gap. The few papers so far about the immune response are mostly hypothesis-generating at this point. Down the line, this will have big implications for vaccine development, which we're all very hopeful for, so hopefully a lot more to come on that.
How long will you continue doing the updates?
Meyerowitz: The next one is May 19th. We're going to do at least a few more. I think we both wrap up at the end of June.
Richterman: We'll keep it going for as long as we can and as long as we think that people are finding it useful.