USA: The RECOVER Initiative - Long Covid research

TSP: 10/6/24 - "How Metformin May Lower Long COVID Risk: Insights from NIH's Dr. David Goff"

'Dr. David Goff, Director of the Division of Cardiovascular Sciences at the NIH's NHLBI, and lead epidemiologist for RECOVER, discusses the study'

'Metformin inhibits protein translation which inhibits that process of viral replication inside the cells and that's one way in which metformin might work - both to help acute COVID but also to Long COVID - if the amount of virus in the body is important in driving the risk of Long COVID through mechanisms related to inflammation, immune activation, auto-antibodies and auto-reaction to those antibodies. Metformin has also been shown to have some direct anti-inflammatory effects to tamp down some of the inflammatory mediators that our cells create when we when we have an inflammatory stimulus like an infection.."
 
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10/19/24, IDTV Week: "The Continued Battle Against COVID-19 | Jeanne M. Marrazzo"

5-minute interview with NIAID Director (transcript below)

Marrazzo: "Long COVID, I think of as one of the most challenging conditions of our time, right? We’re just starting to unravel the mystery of what Long COVID is about - it's pretty clear that for some cases there is persistence of the virus - so, targeting what might be a reservoir either a virus or viral antigens is one strategy that people are looking at. The other is looking at the immune response to the virus - is there this legacy immune response that's continuing to drive inflammation, T-cell exhaustion - all these things that are really coming together to make this syndrome what it is? It also I think is a testament to the fact that if you can avoid getting COVID, you should avoid getting COVID and you should avoid getting it multiple times if you can and you know that means obviously vaccines for the most part.

Host: "So, when it comes to the future down the line not only just with COVID but also new variants as you mentioned are there new technologies I mean what's the major push moving forward to mitigate”

Marrazzo: "So, the major push moving forward is embodied in part by the RECOVER-TLC program which we are taking forward in NIAID, it's RECOVER - Treat Long COVID - the idea behind this to leverage everything we're learning about the pathogenesis to design clinical trials that can be done rapidly - sort of like we did during COVID - so scale them up quickly, make sure you can effectively discard hypothesis once you have a candidate you think might help people - study it, study it and as many people as you need - if it doesn't work, it doesn’t work and move on. So, the tools to look at the immune response are much more sophisticated than they’ve ever been - with tools to detect the virus - in some of these hidden reservoirs for example, like the gut, the brain other places are more sophisticated than we’ve ever been, so we can't overpromise but we can't stop. we really have to keep pushing. I am always hopeful because we have amazing people who are really committed we and especially for Long COVID - there's a very engaged advocacy community of patients, providers who have really, I think, struggled to be heard as an entity so very important to engage them - very important to continue to listen to those concerns and to act accordingly."
 
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Assuming many received this message yesterday, but sharing in case below on RECOVER-TLC submissions:

"The RECOVER-TLC Leadership Team would like to extend sincere thanks for submitting a potential intervention via the online submission portal.

We wanted to provide a brief update that we have received over 220 submissions thus far and are working to categorize them to help streamline review. NIAID has submitted a Request for Information (RFI) that is under review and will be posted soon. Within the RFI there will be a Form any individual can fill out who has interest in serving on an agent review working group.

As a reminder, agents will be reviewed on a rolling basis and every submitter will receive an email updating them on the status of their submission once the information is available. Additionally, the portal will remain open for the foreseeable future – there is not currently a deadline imposed for submissions."
 
9/11/23, Ground Truths: 'Ziyad Al-Aly: Illuminating Long Covid'

“Hopefully the RECOVER folks will take it to heart & will rethink the approach & allocation of funds..what really bothers me is a lot of the money has been allocated to the observational arms.."

“And my argument to them is that actually we can produce the same...We have produced all that evidence for peanuts two years ago. You know, we need a study in JAMA to tell us that, well, long Covid is characterized by fatigue and brain fog. I know that already. I think we did that like two years ago.”

“Well, we need interventional studies. Most of the money should really be allocated to interventions, not really observational arm. And it's not too late to correct course. It's absolutely not too late to correct course.”

“It's great that we had the NIH to allocate significant funds, but maybe a lot of that, unfortunately, has been wasted. But I think we can do much better in getting the point across that this is a really big deal, that so many people, their lives have been changed. We don't have a remedy in sight.”
 
6/6/23, Ground Truths: 'Hannah Davis: A 360° on Long Covid'

Davis: “I think the one I'm most excited about right now are JAK-STAT inhibitors. And this is because one of the leading researchers in viral onset illness, Ron Davis and Rob Phair…”

"Well, I mean, so I think RECOVER really messed up by not putting experts in the field in charge, right? Unfortunately, RECOVER’s our best hope still, or at least the best funded hope. So I really want to see it succeed. I think that they have a long way to go in terms of really understanding why patient representation matters and patient engagement matters.”

“It's been a couple of years, it's still very hard to do engagement with them. It's kind of a gamble when you get placed on a committee if they are going to respect you or not, and that's kind of hard as people who are experts now. I've been in the field of long Covid research more than anyone really I'm working with there.”

“I really hope that they improve the research process, improve the publication process. A lot of the engagement right now is just tokenization. They have patient reps that are kind of like, a couple of the patient reps are kind of yes men. They get put on higher positions and things like that, but I think there's 57 patient reps in total spread across committees. We don't have a good organizing structure. We don't know who each other are. We don't really talk to each other. There's room for a lot of improvement..”

Topol: “And yeah, so lack of treatments. And then the first intervention study that was launched incredibly was exercise. Can you comment about that?

Davis: "It's unreal. You know, it just speaks to the lack of understanding the existing research that's in the space. Exercise is not a treatment for people with PEM...I get that it's hard. I get that when you see patients on the screen, you think that they're fine, and that's just how they must look all the time. But RECOVER doesn't understand that."

Topol: “When I did sit down with Gary Gibbons recently and he was in a way, wanting to listen about how could RECOVER fulfill its goals - and I said, well, firstly, you got to communicate and you got to take the people very seriously, not just, as I say, put them at the kiddies' table - and then really importantly, why isn't there a clinical trial testing any treatment? Still today, not even a single trial has been mounted. There's been some that have been, you know, kind of in the design phase, but still not with a billion dollars."

All that's been done is basically following people with symptoms as already had been done for years previously. So it's just so vexing to see this waste and basically confusion that's been the main product of RECOVER to date and exemplified by this paper, which is apparently going to go through some correction phases and stuff. I mean, I don't know, but really, whether that's going to change the two institutes, it's NHLBI, the Heart, Lung, and Blood, and the Neurologic Institute, NINDS, that are the two now in charge of making sure that RECOVER, recovers from where it's right now.”

“I think we're really struggling because, yeah, there's gonna be five trials, as I understand it, and that's not enough. And none of them should be behavioral or lifestyle interventions at all. You know, I think it also communicates just the not understanding how severe this is."
 
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9/20/23, TLC Sessions - Living with Long Covid: Episode 63: Eric Topol

Topol: “Today I got called early this morning by the HHS, the government of the US, because they were gonna be making their big announcement today about starting clinical trials, which is about at least a year or two years overdue…they were trying to make sure that I didn't say anything negative about their efforts, which I have in the past. So the future, we could be much further along, but we have not one single validated treatment for all the different aspects of long Covid. And it's so vexing. So much of this could have been accelerated.”

“we're working at glacial speed. And actually, ironically, Julia wrote today in LA Times op-ed about her experience and how desperately we need, urgently pressing need for some treatments. And so, no, we haven't really made any progress. It's unexplainable that we didn't rise to the occasion. So in the US, they've dedicated a billion dollars, which is, for medical research, that's a pretty good chunk of funds, and so-called RECOVER. So it was the right idea, but it has basically poorly executed.”

“They're great, and they have a seat at the table of RECOVER. And I said to Hannah, it's kind of like the kiddie table. You know, when you have a gathering and you have the adults at one table, and you have the real Long Covid people at the kiddie table. That's kind of what it's like, is their input isn't getting the highest level of respect, and it should. And it goes along with the trials that were announced today. There were just two, one for cognitive decline and one for Paxlovid or persistence of virus.”

“The only reason today I was at all interested is because there hasn't been any clinical trial for the billion-dollar investment. Not a single one.”

“But it's amazing that here we are, 2023, and we have nothing. And we have tens of millions of people who are affected. I know the medical community moves slowly, but I've not seeing anything quite mismatched between desperate unmet need and action, even when there's allocation of big funding.”

“So we've had more writing, but not in the way of action. One thing I would add, you know, that Long Covid review that we did, it's near 1 million downloads now, 980,000. I've never seen anything like this in my career. I've written, I think, 1,300 peer reviewed papers. So the interest in it is intense. It just goes along with the tens of millions of people who are looking for help, either for themselves or for loved ones or friends or whoever. I've never had a paper in my whole career that's drawn this much attention.”

“That's what I told the HHS this morning. I said, you're asking, they only work through clinics. You have to show up. I said, you're asking people that, some people, they barely can get out of bed. They can't even do their daily life activities. You're asking them to go through all these hassles when you could do so much of this remotely”

“They don't get it, but that's absolutely true. That's the future of medical research. The only reason you have to come in is if it was an investigational drug that wasn't approved or something like that."

“Well, in the US the barrier has been this RECOVER organization that's unwilling to go digital, not really listening to the patients, citizen scientists, if you will. I think they're not listening as much, but at least they do have them involved. And that's a step in the right direction. They've gotten the message from many of us that they better get moving here because the frustration level is mounting past the boiling point.”

"We screwed it up here. The billion dollars is great. And thank goodness to Francis Collins, the director of the NIH, who made that happen. But he's no longer the director of the NIH. And it was basically given to two institutes, within NIH to execute the heart, lung and blood, it's called NHLBI, and NINDS, which is the neurologic institute. Those are the two institutes that were charged to getting this done. And what they've done is they've gone through the old playbook, get a bunch of sites, give them a lot of money, and then wait X number of years to get something. And so this old playbook, not using any digital, spending all sorts of money, not doing trials, just doing observational, the first things they've done is the symptoms. We know the symptoms. We don't need to spend another year to look at the symptoms. My goodness, there's been enough publications, there's been as many publications as symptoms times 10. So we don't need that.”

“I guess your question is, does it get the respect, the acknowledgement of how big an issue this is? And the answer is no. We also have doctors dissing me. We have people who I used to think were credible researchers who are saying these are just malingerers. It's psychosomatic.."

“I'm optimistic we'll get there, but it isn't going to happen by natural. It needs help. You know, just like the whole ME/CFS world was ignored for decades, and other post-viral syndromes that converge with Long Covid, there weren't the numbers of people. There weren't the millions upon millions. But these people didn't get better naturally, and the work that's being done here should help, should spill over across the board for post-viral clinical impact by force.”
 
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12/22/22, TLC Sessions - Living with Long Covid: Dr. Benjamin Natelson

“In the spring of 2020, I started writing grants to NIH because I saw a tidal wave of illness coming with no one being prepared. NIH said, we don't care, that's not our problem right now”

“They've started a program called RECOVER. And what RECOVER is, is $1.1 billion to understand Long Covid. I guess the only problem I see with RECOVER is that it's a top-down program. The NIH usually is a bottom-up program. Researchers like me have a bright idea, lay out the logic, compete with other people, and if you're lucky, get the grant, do it. Here, it's really administered top-down. So there are sites that make decisions about who's going to do what.”

“In other words, to get a therapeutic trial approved through RECOVER, that's a big process where an individual puts forth an idea and then it's reviewed by a number of committees and then it goes up the flagpole.”

“I'm optimistic that this huge investment that they finally made here in the United States to fund this RECOVER program is going to bring a lot of knowledge. It's going to help us understand the disease. I'm a little disappointed because the powers that be don't see the value of including a group of patients who have ME/CFS and not Covid to understand how the two may be the same or different. That's why I'm so thrilled with our imaging grant that was funded.”
 
11/1/23, TLC Sessions - Living with Long Covid: Episode 65: Dr. Amy Proal

“Now we are highly encouraging NIH to just create NIH grants for Long COVID that anyone can apply to, any team can. RECOVER is just a select group. One of the big problems that we face right now is that the NIH is not funding Long COVID research very much. There's not even a very reliable Long COVID funding mechanism, which is crazy.”
 
NYU Langone: 'Telehealth tDCS Shows Promise for Neurologic Symptoms of Long COVID'

“This is the first nationwide, controlled clinical trial to directly address PASC-mediated cognitive dysfunction.” - Leigh E. Charvet, PhD

“Our goal is to provide patients with long COVID an accessible, evidence-based treatment approach that will improve their quality of life.”

'The NIH recently launched a larger study that aims, in part, to clarify the method’s utility. The RECOVER-NEURO trial is testing tDCS alongside other interventions for cognitive dysfunction related to long COVID, including brain fog, memory deficits, and difficulties with attention and problem-solving.'
 
11/3/22, Open Mics with Dr. Stites: Show Me the Science: National Study on Long COVID

“Joining us virtually from Washington, DC is Rear Admiral and Assistant Surgeon General and Deputy Assistant Secretary in the US HHS for Science and Medicine, Dr. Michael Iademarco.”

Host: "“What are some of the similarities between long COVID and other infection associated conditions?”

Iademarco: “When we think about long COVID, it depends on how you categorize it. There could be up to 40 different conditions, and some of them share symptoms with previously recognized infection associated conditions. One of them, for example, is ME/Chronic Fatigue Syndrome."

Another is the Dysautonomia, which I mentioned previously, and Cognitive Impairment, which is often termed Brain Fog in the media or lay press. And so there are examples of conditions that share symptom overlap, to a significant degree, to what we're seeing definitively in patients with long COVID. And then there's other conditions, you know, viruses, there's all different types of viruses and a few bacteria that cause these more chronic conditions.

For example, Lyme disease or West Nile virus, etc. A number of these conditions we know cause a whole host of symptoms. And so when you compare the vast array of perhaps over 200 symptoms that have been categorized so far with long COVID, you can find conditions or sub conditions that share overlap with these other conditions.”

“So if we can understand and study the basic causes of long COVID, it's hoped that we'll actually be able to benefit, not just patients prevent and help patients with long COVID, but the understanding and the therapies could extend to people with these other conditions.”

Host: “The cognitive issues, all these symptoms overlap with other health disorders like chronic fatigue syndrome as you talked about, and myalgic encephalomyelitis. So what can we learn from these other conditions as well?

Iademarco: "Yeah, I think that's another point that we're trying to do from a federal coordination view. So you know how in different areas of medicine, we have sort of separations between different disciplines, cardiology or psychiatry, etc. And so when you think about all those other conditions that we've just been talking about, they have their own experts."

And because long COVID and how long COVID is new, there's a new emerging set of experts. So one thing we try to do is to get these experts together as quickly as possible, whether it's a research study or trying to design best practices. We're working closely with professional societies to also help with some of these bridges.”

“In terms of the causes with long COVID, I think there's two emerging tracks that people are thinking about. One is the virus causes direct effects on tissues and cells throughout the body, causing the damage leading to the symptoms and then the condition. And then the second theory or second bucket of theories is that the virus causes inflammation in a complicated way where that the virus may settle down or be eradicated or eliminated, but the continued persistent inflammation goes on to have bad effects on the body. So two examples might be that in the first category, the virus is affecting, say, blood vessels.

There could be small clots, and this could be contributing to the cognitive impairment. That's just one of several ideas in that area, where in the second category, the virus is causing an immunologic reaction, and then that immunologic reaction hits the pancreas and then causes diabetes. So these are the two major pathways. But I think in the end, we're going to find multiple pathways in terms of cause and effect for long COVID.”

Host: "“Joellen wants to know, could this type of research for COVID and long COVID help with research for other conditions like fibromyalgia? Are there similar characteristics with fatigue?”

Iademarco: "Yeah, in the RECOVER studies, actually, one of the challenges with the RECOVER studies is defining what we call the endpoints. That is, you do the study and you have to measure something at the end to see if there was an effect. Did the patient get better or not? Did the cancer go away or not? With long COVID, because it's new, defining these measurements to determine whether a certain treatment has been successful or not, or effective or not, has really been challenging. And fatigue is one of them.

It's hard to measure fatigue from a objective machine-measured endpoint or testing endpoint. But the NIH and their partners in academic centers, relying on previous literature from other fatigue conditions, including fibromyalgia, have come up with ways that they're going to measure fatigue. So yes, fibromyalgia includes overlap with these long COVID conditions. Fatigue is one of those important symptoms. And measuring it is really important. And people, everybody wants everything to go really, really fast, which is very understandable. But at the same time, we have to get it right so that we end up with meaningful results at the end, so that can lead to approved tests and treatments.”

“Where it's more challenging are the conditions in this third bucket that we talked about in terms of chronic fatigue syndrome, dysautonomia or POTS and the cognitive impairment, along with other autoimmune types of conditions. There things are less well defined.”
 
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11/15/22, PulmPEEPs: “Long COVID Roundtable”

“Jason Maley. Jason is an Assistant Professor of Medicine at Beth Israel Deaconess Medical Center and Harvard Medical School. He is the Director of the BIDMC Critical Illness and COVID-19 Survivorship Program, and the Co-Chair of the American Academy of Physical Medicine and Rehabilitation, Postacute Sequeleae of SARS-CoV-2 Infection. He is NIH funded to study post-COVID patients,”

Maley: “Another example might be the unique aspect of severe persistent fatigue…that's very unusual and a unique aspect that we see with post-viral syndromes like ME/CFS and with long COVID."

“My takeaway is really this experience with working with patients with long COVID has brought me back to the core aspect of medicine, which is a relationship between a clinician and a patient and being thoughtful about how to help that person in the things that matter to them. And listening more than talking.”
 
6/12/21, Coronavirus (COVID-19): “What Do We Know about Long COVID?"

“And now with this infusion of NIH funding, I'm hopeful that at this time next year, we'll have even more updates to report”

“A lot has also been raised by, again, the patient community about how, and Dr. Fauci himself recognizes it, it's extraordinary how many people with COVID-19 have a post-viral syndrome that's very strikingly similar to myalgic encephalomyelitis or chronic fatigue syndrome.”

“we know from the similarity and the overlap between long COVID and chronic fatigue syndrome, that that can actually set people back. This phenomenon of post-exertional malaise where people feel more tired if they over-exert themselves”

“So it's already known that certain viruses definitely have long-term impacts, and that's why it is critical to really study all of this and put it into context of what's known about other viral illnesses.”

“What is the biological basis of long COVID? And again, maybe this is direct viral toxicity and the vaccine is somehow helping with that. Perhaps it is helping with the auto antibody response. Perhaps it's dealing with a persistent viral reservoir.”

“So our take-home points, you know, the care of patients with long COVID or PASC…this is new and evolving. And we really need a comprehensive, multidisciplinary approach to address these long-term physical, pulmonary, cognitive, and mental health symptoms.”

“So now we're seeing NIH funding, this huge funding push towards long COVID, which is great, which a lot of researchers are saying, we needed this funding last year to study patients as they were coming out last year.”

UCSF Pulmonologist Dr. Lekshmi Santhosh: “That is a huge part of my chats with patients, is telling them, I believe you. And listening and validating their experience. I have heard so many horror stories that just bring me to tears of what patients have been through. You know, being dismissed..”

“the medical community is certainly catching up, but I definitely hear and my heart goes out to people who have felt that they weren't being heard, they weren't being listened to, that they were being discriminated against. So I tell people, you're not alone.”
 
9/23/24, ACSH Science Dispatch: “Have We Pinpointed A Cause Of Long COVID?”

Dr. Chuck Dinnerstein, Director of Medicine at the American Council on Science and Health: “There is an NIH long-term study looking at long COVID..trying to figure out where are the most promising places to look for an understanding and a solution to the problem.”

“I'm sure there will be more on this, because long COVID doesn't seem to go away. Not in terms of just the condition itself, but everyone's always talking about it to some degree.”
 
It's hard to measure fatigue from a objective machine-measured endpoint or testing endpoint. But the NIH and their partners in academic centers, relying on previous literature from other fatigue conditions, including fibromyalgia, have come up with ways that they're going to measure fatigue.
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Maley: “Another example might be the unique aspect of severe persistent fatigue…that's very unusual and a unique aspect that we see with post-viral syndromes like ME/CFS and with long COVID."
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They are still stuck in their monomaniacal obsession with 'fatigue'.
 
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