Podcast: Long COVID-19 can affect every organ system in the body

Jim Dryden (host): Hello and welcome to “Show Me the Science,” conversations about science and health with the people of Washington University School of Medicine in St. Louis, Missouri … the Show-Me state. As we continue to detail Washington University’s response to the COVID-19 pandemic, in this episode, we look at some of the long-range problems associated with the illness. People get very sick, and some become long-haulers. Brain fog, shortness of breath and fatigue have been associated with long COVID since the early days of the pandemic. But Dr. Ziyad Al-Aly, an epidemiologist at Washington University School of Medicine and the Veterans Administration, and his team have found that COVID-19 infection also increases risks for later kidney problems, heart problems, psychiatric problems like depression and anxiety, and diabetes.

Ziyad Al-Aly, MD: We’re no longer talking about long COVID that only causes fatigue or brain fog. And these are potentially irreversible conditions. One could wake up tomorrow and say, “Well, my fatigue is gone. I feel better. My energy is back.” And we see that in the clinic, right? For some people. That’s not a universal story, but these things could potentially improve with time. We’re starting now to uncover long-term consequences of COVID-19 that literally will last a lifetime.

Dryden: And there’s more. Another study conducted at Washington University by pain specialist Simon Haroutounian and his team turned up evidence that people who tested positive for COVID-19 were more likely to report problems with pain and numbness in the hands and feet, a condition known as peripheral neuropathy.

Simon Haroutounian, PhD: We know that several viruses can damage nerves. So when COVID started, we thought that potentially SARS-CoV-2 virus may also interact with nerves and cause some nerve damage.

Dryden: Very early in the pandemic, we first heard about so-called long-haulers, people who didn’t die from the virus, but they didn’t seem to get better either. Since those early days, Ziyad Al-Aly’s team has been studying the medical records of large numbers of patients, and they’ve found that COVID infection seems to affect pretty much every organ system in the body.

Al-Aly: We found that COVID-19 was associated with higher risk of all sort of heart problems, mental health disorders, neurologic disorders, also diabetes and kidney disease. And collectively, what we know from our work and also others now about COVID-19 is that, because of its structure and characteristics and — primarily related to spike protein — how it interacts with different cells in the body, it has a predilection where it can affect literally every organ system in the body.

Dryden: So as you just said, you’ve identified increased risk for heart problems. You’ve identified increased risk for psychiatric problems, like depression, anxiety. Diabetes. Can you, sort of, explain in simple terms how you were, as an epidemiologist, able to kind of connect all those dots?

Al-Aly: Because we didn’t know a whole lot about the long-term ramifications of COVID-19 initially, we started what we called an unbiased approach. We literally wanted to look at the whole gamut, the whole thing, the whole body using an unbiased approach, and so to speak, like leave no stone unturned. And then we did work to delve deeper into the cardiovascular manifestations, that’s the heart manifestations, mental health disorders, kidney disorders, and now, most recently, diabetes. Our approach generally to this is to try to take a group of people with COVID-19 and then compare them to people who did not get COVID-19.

Dryden: The people that you’re studying are primarily in Veterans Administration databases. And I wonder if I’m correct in assuming that they would then tend to be maybe a little older, male. And so we know there are some differences in initial infection, right? Older people tend to get sicker. Some men tend to get sicker than women. Do you think that what you’re seeing in these studies translates to the whole population, including women and younger people?

Al-Aly: I love this question. And thank you very much for asking. So I get this a lot. You guys live in the world of the VA. It’s mostly older guys, and for the most part, white people. There’s very little, or the proportion of Black people in the VA is smaller than the general population. Are your results generalizable? And the answer is yes and no. The devil here is in the details. Because of, really, the big size of our cohort — generally, we have 10% of our cohort as female, but we tend to do studies with millions and millions of people. The last study was at least 8 million people. A little bit more than 8 million people. Well, 10% of 8 million people is 800,000 women. And that’s not really small. I get people saying, “Oh, you only have 20% Black participants in your cohort,” which is totally true. Twenty percent is certainly not the majority, but 20% out of 8 million people is more than 1.6 million Black participants in the cohort. So again, because of the bigness of the study, because of, really, the large number of participants in the study and the diversity of the people involved in the study, we think, actually, the results will likely — will hold more generalizably to the broader U.S. population, and also likely, the global population. And we take very good care to also do what we call subgroup analysis. Because we have big, big numbers, we say, “OK, what if we study only these women in isolation, these 800,000 women, and do a particular subgroup or sub-study to evaluate the risk in them?” And we find pretty much the same thing. And naturally, you can take that to be a study of 800,000 people, and all of it is women. 100% is women, and we find the same thing. So taking together and us sort of working with these data for a long time now, we feel pretty confident that what we find is generally generalizable to other settings.

Dryden: So you see 40% increased risk in this, a 60% increased risk in that. In terms of absolute numbers, if there was a 1% increase, so it’s one in 100, and it doubles, it’s only two in 100. So I’m wondering how significant some of these problems are on a population basis.

Al-Aly: This is an absolutely wonderful question, too. So broadly speaking, on a relative scale, you are absolutely correct that the relative increase in risk is anywhere between 30% and 70% for most outcomes. Now, the question, how does that really translate into absolute numbers? Generally, we feel like long COVID, with its myriad manifestations, that all the sequelae that can happen in people with long COVID, anywhere between 4% and 7%. And some people say, “Well, these are single-digit numbers. That’s not really a very serious problem.” And the argument against that is that, because COVID-19 affected a whole lot of people in the U.S. and a whole lot more, millions and millions more, across the globe, even 4(%) 5(%) or (6%) or 7%, those single-digit numbers that we are reporting, will translate into millions of people with long COVID in the U.S. and many, many, many more around the world. So we think the problem is significant. We’re no longer talking about long COVID that only causes fatigue or brain fog. And these are potentially reversible conditions. One could wake up tomorrow and say, “Well, my fatigue is gone. I feel better. My energy is back.” And we see that in the clinic, right? For some people. That’s not a universal story. But these things could potentially improve with time. We’re starting now to uncover long-term consequences of COVID-19 that literally will last a lifetime, like heart disease, diabetes, kidney disease. These are things that are chronic conditions, certainly manageable, treatable, that can be treated and addressed and managed, but they’re not curable conditions. So even small percentages of people with diabetes or kidney disease, or small percentage of people with heart failure will translate into millions of people suffering from a chronic condition that will literally scar them for a lifetime.

Dryden: What about vaccination? There’s some evidence that people who are vaccinated, though they can get COVID, their infections don’t seem to be as serious. They don’t feel as sick. They don’t end up in the hospital. They don’t die as much. Do you know whether vaccinated people are more protected against some of these long-term effects of COVID?

Al-Aly: This is a very, very important question. I get asked about this all the time by patients, and they say, “Hey, doc, I’m vaccinated. I got breakthrough disease. What about my risk of long COVID?” So we are currently doing these studies, and it’s being reviewed now, and we will release those publicly as soon as we can.

Haroutounian: I’m Simon Haroutounian. I’m an associate professor of anesthesiology at Washington University School of Medicine, and I’m the chief of clinical pain research at Washington University Pain Center.

Dryden: We’ll hear more from Ziyad Al-Aly in just a moment. But first, we hear from Haroutounian, who, with his colleagues, recently found that comparing people who tested positive for the virus to those who tested negative uncovered another possible long-term problem.

Haroutounian: Another potential long-term side effect that our group has identified potentially relates to peripheral neuropathy, or nerve damage-associated pain, tingling, and numbness that affects the hands and feet in those patients with COVID. Several viral infections have been associated with peripheral neuropathy — HIV or shingles, etc. — because we know that several viruses can damage nerves. So when COVID started, we thought that potentially SARS-CoV-2 virus may also interact with nerves and cause some nerve damage. We started a study where we reached out to patients who had a positive SARS-CoV-2 test and compared them to patients who had a negative test, and looked at any potential issues related to peripheral neuropathy symptoms at the time of testing, but also symptoms that lingered for one to three months after the initial infection. Patients who had a positive test were something like threefold more likely to report pain and numbness and tingling in their hands and feet. And it was true at the time of infection or testing. It was true when we asked them, like, two weeks after the initial symptoms, but also lingering effects that continued one to three months after. So in about 6% of patients, the symptoms continued all the way through about two to three months after their initial infection.

Dryden: One of the aspects of this study that I found interesting in reading the paper was that everybody in the study had gotten tested. You’re not comparing COVID positive patients to people who never came in for a test. Everybody either felt they had an exposure or they felt a little sick, and they came in and got tested. So you know you’re comparing COVID positive to COVID negative.

Haroutounian: Now that’s a very good question. In each study, when you’re doing any sort of epidemiological work and trying to find an association between, let’s say, a disease and a certain outcome, you want some sort of control group to see whether whatever you have found is not just a random finding. And one of the ways to select that comparison population is to look at patients who came for or came to test for SARS-CoV-2, but had a negative result on their test. Some of the patients who were tested were because they got potential exposure but didn’t have symptoms, or had to be tested for medical reasons, for example, before undergoing surgery. For us, it was, sort of, the optimal control group.

Dryden: You mentioned shingles, and shingles is recognized as being very painful. But it comes from a virus that causes chickenpox, that zoster virus sits in the nerves for a long, long time before the pain begins. I’m wondering if there’s any thought that this SARS-CoV-2 virus could become more painful subsequently years down the road.

Haroutounian: Indeed, we can only speculate at this point, without really doing that long-term follow-up, and see whether the patient symptoms linger or they get resolved. So we don’t know what the numbers would look like six months after the initial infection or a year after. But in our study specifically, we saw that most patients who complain of those symptoms do have mild to moderate level of symptoms rather than severe disease, at least in the first few months after the infection. I mentioned that HIV infection, for example, is associated with rates of peripheral neuropathy, but for about eight years, people didn’t realize that there is neuropathy associated with it. And a lot of patients went undiagnosed. And, sort of, only quite a few years later, the new studies started looking at, “Oh, there is this particular phenomenon associated with an HIV infection.” And this left a lot of patients undiagnosed and untreated and suffering. And so that was one of those motivators to think, to look at this phenomenon early on to see, is there a signal in SARS-CoV-2?

Dryden: Where Haroutounian’s study involved more than 1,500 people, it’s a rather small data set compared to what Al-Aly has been working with. But he says the impetus to launch those studies really came from a single article he saw in The New York Times.

Al-Aly: When COVID-19 hit, we had a brainstorming session over Zoom with virtual. At that time, we were all sent home, like, “Don’t come. We don’t want you in the office. You need to work from home.” And we had this brainstorming session on, how do we do our part to respond to this pandemic? It was March 2020. We didn’t know about long COVID. We didn’t know that the pandemic is going to last that long. We didn’t know it was going to be that severe. None of this was known to us. But what was known to us is that we — now we’re in a crisis. We’re in a crisis mode. At that time, we — unanimously, all the group members resolved that we were going to identify knowledge gaps that are important to the public, questions that the public care about, and then try to address them rigorously using our scientific knowledge and data. And the earliest work we’ve done was, sort of, a COVID versus flu. At that time, even the president was saying, “Oh, COVID is like the flu, or is even milder than the flu.” And we can actually address this in our data. So we started doing COVID research, starting from that COVID versus flu paper, and then subsequently sort of evolved to study long COVID. The long COVID piece was 100% inspired by the patient community. We did not know that long COVID existed. And I do remember the first time reading an op-ed piece in New York Times by Fiona Lowenstein, in April 2020, where she wrote, “Let’s talk about what coronavirus recovery looks like.” And: “I was young and healthy, had no medical problems at all before March 2020, when I got COVID-19. Weeks after the initial illness, and I’m still having all these problems. Everybody tells you that, ‘If you’re young and healthy, you’ll bounce back. You’ll do fine. This is just like the flu, or even easier than the flu, or milder than the flu,’ yet here I am, young and healthy, 20-something years old in New York City, still profoundly affected by this.” That was eye-opening for me. It was sort of the first report. I was like, “Oh, something here is happening.” At that time, in March and April, we had some cases in St. Louis but not as much. But that was an eye-opening for me, that something is happening in people that is sort of a bit unusual. That report generated sort of a movement. All the patients coalesced around her, responded to her op-ed piece within, literally, 48 hours. And they, to their credit, published their first report characterizing all the different manifestations of long COVID in May of 2020. And that was sort of in our mind a seminal report on — basically gave the condition its name, long COVID. They started referring to themselves as long-haulers. These are all patients. None of them is a scientist, none of them is a doctor. These are all patients. They coined the term long COVID. They started referring to themselves as long-haulers. They were the primary inspiration for us to pursue this work. All of this is really pretty much inspired by them and the problems that they think are important to solve or to address.

Dryden: Assuming — I guess I should knock on wood or something — that we’re on the way back toward something that’s more normal. What do you want to do next?

Al-Aly: I think, whether now or a year from now or two years from now or five years from now, we’re committed to solving problems that the public care about, that the people really care about, that the patients really care about, that are sort of consequential from a public health perspective. So we think the long COVID story is really important, and there’s a lot to address there over the next several years. So definitely, we think that we definitely have a very strong pipeline of research in long COVID. This pandemic is still dynamic. If there are things that sort of evolve a year from now or two years from now that require addressing, we’re certainly, again, very pragmatic into pivoting into things that are really most important to the public, and we will continue to do so.

Dryden: You’ve identified these increases in problems: heart disease, depression, kidney disease, diabetes. From here, what do doctors do? Do you just more closely monitor signs of potential problems in your patients so that you can begin treating them? You have said these are manageable conditions, though not necessarily curable. So what happens? What happens with this information? What do we do with it?

Al-Aly: So generally what we want people to take from this is that COVID-19 is really a risk factor for developing cardio/metabolic disease. And certainly, people with COVID-19 can go on also to develop long-term manifestations in the form of long COVID. A, we want to promote awareness. We want doctors to know that long COVID exists. We want to definitely promote awareness that the condition exists. Patients are suffering and need to be believed. People with COVID-19 are at risk of developing heart problems, diabetes and kidney disease. And we want that to be treated now or thought of in the clinic as a risk factor. So when I treat patients or see patients with COVID-19, those patients need to be seen with that lens and evaluated with that lens. Because those conditions, when identified early, they’re always associated with better prognosis or better outcomes than when you leave them to become even more and more serious problems down the road. These problems don’t manage themselves. They tend to become worse if not medically treated. We think that this is really a consequential problem. It’s going to affect millions and millions of people. And our health systems should be equipped to be able to deal with it. And I think it needs to be taken seriously, because it’s affecting millions of people. And it’s likely to result in a wave of people with diabetes and a wave of millions of people with heart disease and millions of people with kidney disease. And those people need care.

Dryden: Although multiple pandemic-related restrictions are being lifted around the country, and for many people life is returning to something resembling normal, Al-Aly says, for others, it may never be normal again due to heart problems, kidney disease, diabetes, or psychiatric issues that followed their infections. And Haroutounian says he hopes to continue studying COVID-19 patients to learn whether the virus also may cause longer term pain and neuropathy. “Show Me the Science” is a production of the Office of Medical Public Affairs at Washington University School of Medicine in St. Louis. The goal of this project is to keep you informed and maybe teach you some things that will give you hope. If you’ve enjoyed what you’ve heard, please remember to subscribe and tell your friends. Thanks for tuning in. I’m Jim Dryden. Stay safe