A new episode of our podcast, “Show Me the Science,” has been posted. At present, these podcast episodes are highlighting research and patient care on the Washington University Medical Campus as our scientists and clinicians confront the COVID-19 pandemic.
In the year since COVID-19 infections first appeared in the United States, a few things have become clear. One is that many who get sick don’t recover quickly. Even those who don’t have to be hospitalized can experience symptoms that linger. Called long-haulers, these individuals suffer from a variety of issues such as shortness of breath, abnormal heart rhythms, fatigue and loss of the ability to smell. In fact, many people first realize they may be infected with the virus when they notice they’ve lost the ability to taste and smell food. For most, these symptoms disappear quickly, but some people continue to struggle.
Doctors and researchers at the School of Medicine are working with long-haulers to help them deal with these lasting effects of the SARS-CoV-2 virus. In this episode, we’ll hear from ear, nose & throat specialist Jay F. Piccirillo, MD, a professor of otolaryngology and the department’s vice chair for research. He is conducting several studies involving long-haulers, trying to help them regain the ability to smell. We’ll also hear from Amanda K. Verma, MD, an assistant professor of medicine and a cardiologist who normally works with very sick patients whose heart disease has made them candidates for implanted heart assist devices or even transplants. Over the last year, she’s seen many long-haul COVID-19 patients who have developed problems similar to those faced by heart transplant patients.
The podcast, “Show Me the Science,” is produced by the Office of Medical Public Affairs at Washington University School of Medicine in St. Louis.
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, we focus in this episode on some of the symptoms that tend to hang on for a while in people who’ve had COVID-19, sometimes for months. Some people who got the illness at the very start of the outbreak last March are still, for example, having heart trouble.
Amanda Verma, MD: How long do these symptoms last? For instance, I have patients that we are able to manage their symptoms with medications, and I have one patient who had COVID back in March and another who had it in April. And we’ve tried to come off of medications, and their symptoms returned. And so are these going to end up being chronic medical conditions? I don’t know yet.
Dryden: That’s Dr. Amanda Verma. She’s a cardiologist who specializes in heart failure and transplantation. And she’s been working with people who had COVID-19 and later developed heart problems. In some, those problems go away. In others called long-haulers, the problems linger. And Dr. Jay Piccirillo, a Washington University ear, nose and throat specialist says that although it’s been clear for a long time that problems with the sense of smell are a key signal of COVID-19, those problems with smell, which doctors call anosmia, persist in a significant number of patients. And Piccirillo is trying to find ways to help them to smell again.
Jay Piccirillo, MD: For the COVID patient at three months who still has an anosmia, we’re optimistic. And we say, “Look, we know from experience now” — COVID’s only been around for a year — “but we know that people who are suffering at three months still have a good chance of recovery at four months or six months.” But with each passing month, it does become less likely that smell will return.
Dryden: Piccirillo is evaluating various ways to help people regain their ability to smell. In one clinical trial, he’s asking them to rinse their sinuses with a solution containing an anti-inflammatory asthma drug. In another study, he’s asking people to smell certain essential oils every day while looking at pictures of the objects those oils are taken from. He says a large percentage of patients become aware that they have COVID-19 when they realize they’ve lost the ability to smell. Up to a quarter still can’t smell two months later.
Piccirillo: We’ve known for a long time that rhinoviruses and other types of viruses have associated with them anosmia or dysgeusia, the loss of smell, loss of taste, alterations in smell and taste. But the number of people that suffer this with COVID is really unique. And it was something that was recognized quite early when the pandemic began this time last year. Upwards of 80% of people may suffer loss of smell, loss of taste or both as part of the presenting symptoms of COVID. Fortunately, most people have a return of smell and taste, and for most people, it’s pretty quick, within a couple of weeks. But there are estimates as many as 8 to 10% of people may not recover. For those of us who have a sense of smell, we take it for granted. And what we think about loss of smell, we probably think about the inability to appreciate cheese or coffee or maybe wine or vanilla, coconut. But in actuality, the main concern that our patients are presenting to us is the inability to smell things like smoke and natural gas. And the primary purpose of olfaction really is protection in a dangerous world. And when you lose that ability to smell smoke and natural gas, it becomes a very anxious and very upsetting situation. And it’s also true that patients complain about not being able to appreciate food and smelling a loved one. Absolutely, that makes our life so much richer. But at the basis of it, the olfaction system is really an early warning system. Early warning for rotten food, for example. Or as I said, something dangerous, like a fire.
Dryden: This obviously is anecdotal, but I’ve heard from some folks who either are patients themselves who’ve had COVID-19 or are related to a COVID-19 patient, complained that as their sense of smell returns, maybe it’s different than it was before they lost it. Maybe things smell bad or maybe they’re more sensitive to unpleasant smells. Have you seen anything similar to that in the patients that you’ve been evaluating?
Piccirillo: Absolutely. This alteration in sense of smell in the COVID patients is being recognized with more frequency. And again, it seems to be a defining feature of COVID. It’s called the parosmia. It’s a distortion within the sense of smell. And for some patients, it can be so upsetting that they say, “I would rather not have any smell than what I have now.” So you’re right, it starts off with either a decreased sense of smell or a complete loss of smell. In many patients, smell comes back for a while and then they start noticing the distortions. And the distortions seem to follow certain regular paths like, you know, burnt rubber is a common complaint. Sour chicken. Moldy clothes. So there’s a finite, limited number of obnoxious smells that they all sort of report in a similar way, which is kind of interesting. But it does make life very difficult because food becomes difficult to eat because of the smell is so bad. This parosmia, this distortion of smell, is being recognized with more frequency among the long-haulers of the COVID patients who are six, nine, 12 months out from their initial infection.
Dryden: You’re evaluating people, trying to help them regain their ability to smell and to taste. But as I understand it, a lot of this research you’re able to do while patients are still at home, is that correct?
Piccirillo: With regards to in-person research, because of the restrictions on patients coming on to campus and shut down or lockdown. All of us researchers have really pivoted to more of a virtual research platform where, like you say, the patients don’t actually come to the medical center. We don’t actually see them in person. We conduct recruitment via the internet. We recruit through social networks. We have electronic data collection mechanisms. We do send out certain type of smell identification tests. And we even have intervention studies where, again, the patients receive their medication from a research pharmacy out of state. They complete the programs using their home computer. Many patients we have never actually met in person. We talked to them on the phone. We can do Zoom, but in-person research has been severely limited due to COVID. But it hasn’t really necessarily been as bad or as problematic as we thought. It’s actually opened up some new opportunities to recruit patients who might not have been able to make it to the medical center in the first place. So one of our studies, we’re recruiting people from all over America.
Dryden: In some of these patients, we know that they get sick with other things – fatigue, or problems with breathing, those sorts of things. Those do improve maybe six, seven, eight months down the road. Is it possible that the same thing would happen with this anosmia, that even though you don’t want it to last that long, that maybe time will be a healer here?
Piccirillo: There is no doubt that in the short term there is recovery of function. So that, for the COVID patient at three months who still has an anosmia, we’re optimistic. And we say, “Look, we know from experience now” — COVID’s only been around for a year — “but we know that people who are suffering at three months still have a good chance of recovery at four months or six months.” But with each passing month, it does become less likely that smell will return. So at some point it’s probably not going to happen. We don’t know where that point is. Is it nine months? Is it 12 months? I don’t know. But we know from the other viral-associated anosmias that by two years, three years if the smell hasn’t come back, it’s not going to come back.
Dryden: As a veteran user of a sinus-rinse bottle, I found this one interesting. You’re going to be delivering a drug to people and having them rinse their sinuses with it on a regular basis, is that correct?
Piccirillo: Yes. So this is SCENT 2 trial. This is a trial of the drug theophylline, delivered in the nasal saline or nose rinse, like you said. So why the theophylline? Theophylline is a drug that’s been around for a very long time for asthma. And it’s a bronchodilator. It helps open up the lungs, relaxes smooth muscles. But it has some properties with regards to different types of messenger cells that we think might be therapeutic for the COVID anosmia. That trial has now opened up to — we are recruiting people with COVID-related anosmia more than three months duration, and they’ll be randomized to receive theophylline or a placebo as a nasal rinse.
Dryden: The other one involves smelling something while looking at a picture of something, correct?
Piccirillo: Well, that’s what we’re testing. If the combination of smell and vision of the same object that you’re smelling improves the recovery of smell, then just smell alone. So we call that bimodal, visual and olfactory stimulation. So the standard olfactory training is four scents: rose, lemon, cloves and eucalyptus. And the subject sniffs twice a day, 10, 12, 20 seconds each time the four essential oils for anywhere to six, eight or 12 weeks. And olfactory training for anosmia has been around for maybe 10, 15 years. You know, studies suggest it works. There’s nothing absolutely definitive. And a lot of us do recommend it in our practice. The idea is it can’t hurt. It’s thought to work by retraining the brain, the process of neuroplasticity, retraining the brain to smell these odors again. And we think that by smelling, you can retrain the brain. Now, one of the outstanding questions is, are you retraining the brain to smell rose, lemon, cloves and eucalyptus better, but forget about coffee, vanilla, coconut? How generalizable is the improvement in smell? Jim, we asked the patients what smells would you like to pick and train on? The answer was fascinating to us. I thought it might be coffee as a coffee lover. I thought it might be vanilla as a vanilla-bean ice cream lover. It was smoke. The number one odor, smell, if you will, that people wanted to train on and to get better was smoke for the reasons that we talked about before. The sense of smell is first and foremost attached to safety. And these people felt that if they could smell smoke better, they would feel more safe. Unfortunately, there isn’t a smoke essential oil so we couldn’t do that. But it just reinforced to us how important it is for patients to pick what smells they want to train on. The other unique aspect that should be brought up is that half of the group are looking at high-quality pictures of the item, one of four items they picked, and each one of them have high-quality photographs presented on their iPhone or iPad at the same time that they smell.
Dryden: The other half are smelling essential oils while not looking at pictures. The idea is to figure out whether the brain will make the connections better if it has more than one input through the nose and the eyes. And while Piccirillo is working with long-haulers who are having problems with smell, cardiologist Amanda Verma is focusing on those having long-haul heart problems including fatigue, shortness of breath, rapid pounding of the heart, and chest pain.
Verma: The other things I would add to that list are either low blood pressure or high blood pressure would be the other things that we see as well.
Dryden: Is there a course of how the virus affects the heart if it’s going to? I mean, a standard way in which those who are going to have heart problems tend to develop them? Or is it all over the map?
Verma: It’s a bit over the map, but I also think it’s a bit over the map because we just don’t have enough information yet to know exactly the course that it follows. In the studies that have been done, we do know that even in patients who’ve had COVID that don’t have a primary cardiac manifestation when they are acutely infected, meaning that they go to the hospital and they have pneumonia-like symptoms. And they don’t have issues with a pounding heart rate or high blood pressure or low blood pressure. When they’ve studied those patients, and in the unfortunate case of when patients have died from COVID and they look at the heart, there are traces of the virus that can be found in the heart. So we know that it is affecting the heart. But the question is really what does that look like and how will it manifest later on, if at all? And so some patients, what we’re seeing is that they don’t have any cardiac symptoms whatsoever. But there are other patients where they had a very mild course, like I mentioned, with maybe just a fever or a few days of fatigue. And then four to six weeks later, they’re coming in with headaches. And we find that they have new onset high blood pressure or heart rhythm abnormalities like atrial fibrillation or really high heart rates that are at normal rhythm.
Dryden: We don’t want to worry any people, but you just said four to six weeks. After six weeks, are you out of the woods, or if you’ve had COVID, is this something that should be checked out as perhaps annually at your physical or something?
Verma: I think in general, the pattern that I’m seeing is that if people are having these long-haul symptoms in general, it’s happening between four to six weeks that they’re still having symptoms or they develop symptoms. But there’s not really a textbook that anyone is following. And so there are always exceptions to that rule. I have some patients that are developing these symptoms months after and some that develop them earlier. And so there’s not really any hard and fast rules. But in general, most of them are having these symptoms in that four- to six-week time period after their initial infection.
Dryden: Is there an understanding yet of how the virus is affecting and infecting the cardiac tissue, or are these secondary effects that maybe it’s not the virus, but maybe it’s an immune response or something else that’s going on to affect the heart tissue?
Verma: That’s a great question. And I feel like I’m a broken record here, but we just don’t know. I think that those are all hypothetical possibilities. And there are studies, like I said, that show that it directly, the virus, can be detected in the heart and that in itself can cause heart damage. But it, like you said, also creates an immune response and that can also have effects. The other leading hypotheses are that it affects the autonomic nervous system, which is that system that provides you that adrenaline rush. And so there’s some question of: Is the elevated heart rate that you have afterwards, is that just an over-stimulation of that nervous system that’s causing that? So people, for instance, can be sitting down and they have a normal heart rate. What’s normal is that you get up and you walk and your heart rate goes up a few points. But in these patients, it’s almost that they have an over-exaggerated response. And so their heart rate goes from a normal to doubles instead of just going up a few points. And then the other thought process and hypothesis that researchers including our team is looking at are endothelial dysfunction, which is the lining of blood vessels. Which is really important in terms of managing blood pressure and a lot of the response of the body, and thinking that that might also have an important role in why certain symptoms develop over time.
Dryden: How do you study something like that? Do you just monitor the blood pressure of people who’ve had COVID, or do you do some intricate lab testing to to figure that out?
Verma: So right now what we’re doing is we’re doing just basic lab testing in terms of checking inflammatory markers, checking blood pressure in different positions with patients, putting monitors on patients to look at their heart rate over the course of several days while they’re doing their normal activity to make some of these diagnoses. But to actually study the mechanism for why this develops is a little bit more challenging and something that we’re working with some of our basic scientists to see how we can better study this in patients. And it’s not something we’ve had all the details worked out yet, but we’re hoping to better understand the mechanism.
Dryden: You know what buildup of plaques in the arteries in the heart can do. You know what electrical problems can do. In this case, do you just use the same treatments because that’s what you’ve got?
Verma: It’s a challenge, and it is a little bit of trial and error. We do use some of the same treatments we know that work for other viruses or similar conditions. For instance, when the virus causes myocarditis or actual direct damage to the heart muscle, we infer a lot of the information that we know about other viruses that can do that and treat it in a similar way. I’ve had some patients, though, that don’t respond to the typical treatment that I’m using for a different or similar problem. And so then it is trial and error. And it’s a lot of discussion with the patients about, “We’re going to try our best to help you feel better, but it may take some time because we’re learning right along with you about what works and what doesn’t work and how to make you feel better.” It’s a challenge and there’s a lot of counseling involved. But I find that most patients are very receptive of any type of treatment that we can offer and are very understanding that we are in uncharted territory. And so there is going to be a little bit of learning together as we approach their problems. While we can use some information from other viruses, on the cellular level, this is acting differently. So it begs the question of on the more clinical level, is it also going to act differently? Which is something that we always keep in mind when we are treating these patients. Even though the rate of infection is going down, I think that we’re still seeing this high burden of people with these long-haul symptoms. And the other question that we all have is how long do these symptoms last? For instance, I have patients that we are able to manage their symptoms with medications. And I have one patient who had COVID back in March and another who had it in April. And we’ve tried to come off of medications and their symptoms return. And so are these going to end up being chronic medical conditions? I don’t know yet, but my fear is that maybe these are going to be chronic conditions that people are going to live with.
Dryden: Neither Verma nor Piccirillo know exactly how to restore their patients to a pre-COVID way of life, but they’re working hard to see how — or whether — that can be accomplished. “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 enjoyed what you’ve heard, please remember to subscribe. And thank you for tuning in. I’m Jim Dryden. Stay safe.
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