As part of the celebration of U.S. Medicine’s 60th anniversary, we will profile some of the remarkable achievements in federal medicine over the past six decades. In the second of that series, we spoke with Ziyad Al-Aly, MD, Director of the Clinical Epidemiology Center and chief of Research and Development at the VA St. Louis Health Care System and Assistant Professor of Medicine, Washington University in St. Louis School of Medicine. We spoke to Al-Aly, who was recently named to the TIME100 Most Influential People in Health of 2024, about the VA’s groundbreaking work on so-called Long COVID.
Ziyad Al-Aly, MD, Director of the Clinical Epidemiology Center and chief of Research and Development at the VA St. Louis Health Care System and Assistant Professor of Medicine, Washington University in St. Louis School of Medicine.
ST. LOUIS — By March 2020, the SARS-COV-2 virus had reached every inhabited continent on the globe, with devastating impact. In response, the U.S. and many other countries entered lockdowns to slow the spread and reduce deaths from the virus. At the St. Louis VA, researchers looked inward to identify ways to make a difference to a nation, to a world, in crisis.
U.S Medicine: How did your work at the VA lead you to tackle long COVID?
Al-Aly: We started seeing that the nation was in crisis mode, and we started asking ourselves how do we, as a bunch of scientists and clinicians and doctors, help? And the answer was, we would need to use our scientific data and scientific knowledge to identify questions that the public really cares about and address them and answer them.
So we were trying to understand what COVID is, and then we started hearing from patients, some of them veterans and nonveterans that that they were experiencing all these health problems that at the time we didn’t even have a name for it. There were all these lingering problems, lingering respiratory problems, brain fog, fatigue, all these issues.
So we asked, what can we do to help understand what that problem, and that launched us on a trajectory to understand long COVID and to research it. At that time, we didn’t really know much about COVID or long COVID; we just felt we are a nation in crisis and we need to do our part. Metaphorically speaking, the house is on fire, and what do you do? You go get a bucket of water and then start working. You have to do your part. Research was our bucket of water.
We wanted to know more about COVID. How does it harm the body? We started there, and then that led us to listen to more veterans and they were telling us we’re also having these lingering health problems. We have this brain fog, we have this fatigue, and at that time, we didn’t even we didn’t even have a name for it.
USM: When did “long COVID” come into use?
Al-Aly: The first known use of long COVID was on Twitter by an Italian archaeologist, Elisa Perego, in May of 2020. So that was the first time it was coined, and the community started using the term “long COVID,” and then they started referring to themselves as long haulers.
USM: How is this so different from earlier SARS viruses in terms of its impact on so many organ systems? We thought of this as a respiratory virus. Obviously, it’s much more than that.
Al-Aly: We thought of it initially as an acute respiratory virus, as seen in the name SARS [severe acute respiratory virus]. The more we learn about COVID itself, and the more we learn about long COVID, it’s very, very, very, very clear to us that it can affect multiple organ systems, and so SARS is a misnomer.
COVID and long COVID are a multisystem disease or multisystem disorder that can affect nearly every organ system. There are people with brain fog; there are people with fatigue and post-exertional malaise. Some people have cardio or Postural Orthostatic Tachycardia Syndrome (POTS), and they have this fast heart rate, cardiovascular or heart rate or heart problems.
Different people manifest differently and, while brain fog and fatigue are cardinal manifestations, long COVID could be about 200 symptoms, literally, spanning all organ systems.
USM: What causes that range of symptomology?
Al-Aly: It may have to do with the virus itself or the immune response to it. It’s a novel virus, and our immune systems responded to it with a sort of intense inflammation. I tell patients sometimes that it’s like a scorched-earth strategy, where the immune system reacts to it so violently to destroy the virus, but then lots of other organ systems are destroyed in the process. I think we’re very, very clear now with the benefit of hindsight that this is definitely not a respiratory virus. It is certainly a multisystemic virus and can affect nearly every organ system.
USM: An infectious disease specialist mentioned that D-dimer tests and other indicators of clotting were extraordinarily high with SARS-COV-2. What causes that?
Al-Aly: COVID increases the propensity of blood clots. Those can be big clots that occlude big vessels, of course, but some people form micro clots. These tiny teeny, teeny, teeny, small occlusions of the vessels can sometimes be in your brain or somewhere else. Actually, it can explain why some people have cognitive deficits or brain fog that may resolve with time. Once the clot passes or the body is able to dissolve the clot and open that passageway, then the function in that area is restored.
The clots are even smaller than the ones in a transient ischemic attack (TIA). They occlude a tiny vessel at the very end of the capillary network that may result in hypoperfusion or decreased blood or oxygen supply to some areas of the brain, impairing memory and attention, recall and executive function. Brain fog is a colloquial term and sort of broad but, in reality, different people have different levels of cognitive impairment and some of them improve fairly quickly, while in some of them it takes weeks or months to sort of get over it.
USM: Were you surprised by your findings that vaccines reduce the risk of long COVID by more than 70%?1
Al-Aly: Not really. We knew that vaccines reduce the risk of infection, and we knew that the vaccine also suppresses the viral load, enhances the ability of the body to clear it faster and reduces the severity of acute infection. So it made sense to us that the vaccine reduces the risk of long COVID. I wouldn’t say we were surprised, but we were happy with the news because, most of the time, with this pandemic, I was telling people bad news. This was actually the first time we had good news. I was really happy that something works, it doesn’t eliminate the risk 100%, but it reduces the risk substantially.
USM: Can you talk about reinfection and how that affects risk?
Al-Aly: If you’re not taking steps to reduce the risk of reinfection, you’re just playing Russian roulette.
It is possible that, if you had a mild first case, the second one will also be mild. But it’s also possible that the second one will land you in a hospital or an ICU bed. Especially for older adults, you’re playing with fire. I think being cautious about COVID and testing for it and also getting antivirals is really very important, especially in older age groups. Even people in their 30s and 40s and 50s, I tell them to be cautious; it’s not a guarantee that, every time you get this, you’re going to dodge the bullet.
The infection is consequential, and reinfection contributes additional risk. Two hits are worse than one; and three hits are worse than two.
USM: Do you see in multiple infections a more-serious impact on the organs that are affected, or are different organs affected depending on different strains?
Al-Aly: The risk is cumulative, and different strains have different manifestations and we saw a lot of pulmonary and cardiovascular problems with the ancestral strain, and now we see a lot more GI and metabolic complications with omicron. Think of it as each variant has its own kind of personality or its own risk profile. And, while we while we put them all down as COVID, they’re actually not exactly the same; they’re not identical. I tell people that, if COVID were a dog, the ancestor could be a German shepherd, and the new strains could be a chihuahua or a golden retriever. Do they all fall under the same umbrella of dogs? Yes, but are they all identical and have the same personality? No, no, no, no.
USM: Is that variance why we don’t have continuing protection from COVID-19 as it mutates?
Al-Aly: This is exactly one of the reasons, and the other reason is that vaccine immunity wanes over time. If you had immunity against Alpha, it doesn’t really mean you have immunity against the KP viruses that are circulating right now. And you never know when the Rottweiler strain is going to show up!
USM: What progress have we made on treatments for long COVID?
Al-Aly: There are no FDA-approved treatments for long COVID, though people are working on them, but there is a lot more we can do now in clinics. We manage patients symptomatically, for example, people have a fast heart rate as a result of COVID could be given beta blockers. Some people have sleep problems, and there are medications for that. Some people have what we call mast-cell activation syndrome, or MCAS, so we give antihistamines. Depending on what type of long COVID they have, if they have MCAS or POTS or other manifestations, we treat those presentations. I have to emphasize that none of these modalities have been approved by the FDA for those indications.
This is where we are. There are zero FDA-approved medications for long COVID. In the clinic we do these things to try to help our patients with their symptomatology.
USM: That makes sense when you say it’s 200 different diseases in some ways, so it is hard to get a treatment through clinical trials and show that it works for everybody.
Al-Aly: Correct, and this is why we advise that clinical trials should focus on phenotypes. For example, we need to do clinical trials to figure out how do we address brain fog? There things that we can do to try to ameliorate or improve brain fog. There are clinical trial for POTS, specifically, and for MCAS.
Just doing clinical trials for broad long COVID would not work because it’s so heterogeneous. You literally have 10 patients in a room with long COVID, and every one of them will have a different set of symptoms, right? This is why trials have to be careful and define trial inclusion for specific types of long COVID to hopefully be successful.
USM: Does Paxlovid reduce the risk of having long COVID?
Al-Aly: In the acute phase, when people take it when they get infected, that reduces the risk of long COVID. Now, if somebody already has long COVID, will it work? There was a trial was done, and it did not work for people where they have established long COVID. I don’t think that really closed the door on the idea of Paxlovid, but in that specific trial, it did not work.
USM: But, if you take with the initial infection, it does provide a benefit?
Al-Aly: If I get if I get COVID today, the first thing I’m going to do is call my provider. I’m going to ask her to please prescribe it for me, because I know it reduces my risk of long COVID.
USM: So, even if you don’t have a bad case of COVID-19, you should get Paxlovid?
Al-Aly: Yes. The data tell us that Paxlovid reduces the risk of severe acute disease and also reduces risk of long COVID. It is a medicine that has side effects. It does have drug-drug interactions, so patients should talk to their providers about whether it is right for them.
USM: What do you see is the biggest challenge today facing the VA and other large health systems in managing patients with long COVID?
Al-Aly: First of all, I personally feel that the VA has done an amazing job. You know, we have Long COVID clinics throughout the VA system. There’s at least one in every VISN.
I think the major challenge is really continuing to wrap our head around it. I literally live and breathe long COVID. I’m thinking about it and write about it and research about it and do interviews about it, and there’s still a lot to learn and understand about long COVID. We need more understanding of long COVID.
Obviously, as we pointed out, there are no FDA-approved treatments, and that’s also another challenge. We have people showing up to clinics and saying, “I want a blood thinner, anticoagulants,” and [the] like, so we need more trials in this area to help us understand, is the risk worth it, is the benefit going to outweigh the risk? So we need data on that. Treatment is really important. We’re three years in and have no FDA-approved treatments. That has to change.
I think the other one is really pandemic fatigue and the idea that this challenge, that COVID, is behind us and is no longer a threat. People are less likely to get the vaccine. We need to counter that with patients, with veterans and with too many community providers. It is also important to say, “You may see it that way, and I understand pandemic fatigue, and I definitely feel you, because we’re all sick and tired of COVID and the pandemic. I understand you. But vaccines really work and we have to try to continue to optimize vaccine uptake and use of anti-virals.”
This is not a problem for the VA only; this is a problem for all of us as a nation; it’s a global problem. At the university right next door, there are also long COVID clinics that have the exact same struggles that we have. This is a ubiquitous struggle in every clinic throughout the nation. People want to put it in the past, but we still have people with COVID and in the ICU in the middle of the summer.
USM: The VA often develops clinical pathways or algorithms to guide treatment, where, if your patient presents with these symptoms, do X. Are those in development for long COVID?
Al-Aly: Yes, we have clinical guidelines for long COVID, and that’s helpful. As we’re learning more, we’re certainly incorporating all that knowledge. I think from that perspective, we’re keeping up to date and keeping our community of providers apprised of all the developments for long COVID.
We have calls that happen on a recurring basis at least twice per month. Here at the St. Louis VA, I run a monthly lecture series to educate the whole VA nationwide on COVID. We host world leaders to try to talk about COVID mechanisms, treatment, different aspects of long COVID, such as dysautonomia, POTS, the biology of brain fog, treatment for brain fog—all of those things. Leaders from throughout the world, from London, from Oxford University, Harvard—everywhere.
There is a lot that we do to try to make sure that our people are survivors and providers are in touch with the latest science, the latest findings, the guidelines, to make sure that we are keeping up to date with an evolving field, and that is literally changing daily.