Long Covid, Symptoms, Diagnosis, and Prevention

Ziyad: And people have really significant long Covid—there are about 20 million Americans who are suffering from the condition today.

Brent: 20 million people in the US today, we believe, have long Covid currently. Correct?

Ziyad: Correct.

Brent: Welcome to Death Clock. I'm your host, Brent Franson. Today we speak with Dr. Ziyad Al-Aly about long Covid. Dr. Al-Aly is the director of the Clinical Epidemiology Center at the VA Saint Louis Health Care System. He's also the chief of research and education service, and he was named to Time 100 Health in 2024 for his work on long Covid.

Brent: He is one of the top long Covid experts in the world. This episode is really a deep dive on long Covid. We talk about how it's diagnosed, what its symptoms are, and what percentage of people it impacts. Some of the skepticism around Covid. It's really top to bottom on long Covid. And it's so important that we understand this topic because long Covid, as you'll hear, does not sound fun.

Brent: It's something that we want to avoid. So I found it really useful to be much more educated on it. I hope you enjoy it as much as I did.

Brent: Dr. Ziyad Al-Aly, welcome to the show.

Ziyad: Well, thank you for having me. Delighted to be with you.

Brent: So today we're going to talk about long Covid. You're one of the top long Covid experts in the world, so I'm excited to jump into this. I think my own personal arc on Covid was taking it very seriously at the beginning, and now I feel like it was a little overblown and I've been taking it less seriously.

Brent: But what I expect is going to happen in this conversation is that I'm going to end up somewhere in the middle. The pendulum will swing back in the other direction over the course of this conversation. So let's see what happens. In any case, I'm excited to know more about long Covid, what it is, and how we should think about it.

Brent: But first, can you give us a sense of your bio, your background, and how you came to be focused on this topic?

Ziyad: Sure. I'm a clinical epidemiologist and also a nephrologist, a kidney doctor. My research program focuses on understanding diseases from big data. So we use very large datasets from millions of people, usually from large electronic health records, to try to understand disease processes. When the pandemic hit, we initially focused on understanding Covid because that was the new kid on the block.

Ziyad: And we wanted to understand what Covid was doing to people. Then we started hearing from the patient community that they were not recovering from an acute Covid infection—that several weeks after the initial infection, they were having problems. So we decided to focus on that. At that time, the condition did not yet have a name.

Ziyad: It actually was not yet named "Long Covid," but we decided to listen to those patients and focus our research program on understanding what was happening to them. That led us on a journey to understand long Covid.

Brent: Let's talk first about the basics of what Covid is and how it's different from other coronaviruses. As I understand it, the common cold can be a coronavirus, but it's different from Covid-19. Can you give us the very basics on what Covid is and how it's different from something like the flu or a seasonal cold?

Ziyad: Sure. What distinguishes Covid from other viruses is first its novelty. It was not previously encountered in humans before late 2019 or early 2020. No human on Earth had previously encountered Covid-19, so human immunity was not developed against it. It emerged and became the pandemic that it is.

Ziyad: The second property of Covid is its scale. Every year people get infected with the flu, but over the past several years, Covid was truly of pandemic proportions.

Ziyad: In the early days and years of the pandemic, when we did research to compare what happens to people with Covid versus the flu, it was very clear that Covid was killing a whole lot more people and putting a whole lot more people in the hospital.

Ziyad: Over the years, that has changed so that it is now almost on par with the flu, and in some seasons, maybe a little milder. Nevertheless, Covid still presents a serious problem. It can lead to significant disease, put people in the hospital, and in some cases lead to mortality.

Ziyad: Most importantly, what we worry about are the long-term ramifications of Covid-19 compared to flu and other viruses. It seems to have a higher probability of leading to long-term illness in the form of long Covid.

Brent: To recap: our physiology and immune systems had never seen Covid before, so when we first encountered it in 2020, it was much deadlier than the flu and caused a global pandemic. But now, depending on the season, it's about as deadly or less deadly than the flu.

Brent: Why is that? Why did it become less deadly?

Ziyad: That's exactly right—that's a beautiful summary of the status of things. There are two key reasons why it has become less deadly. One is that the virus itself has changed over time. While it's still SARS-CoV-2 (the scientific name for the virus behind Covid-19), it has evolved.

Ziyad: It has dramatically changed. I give the example of a dog: maybe it was a German Shepherd initially and now it's a Chihuahua. Are they both still called dogs? Yes, a German Shepherd is a dog and a Chihuahua is a dog, but they have completely different personalities.

Ziyad: It's totally different. Covid-19 is the same way; it has evolved over the years. Is it still Covid-19? Absolutely, it's still SARS-CoV-2, but it's very different. The second key change is that people have developed immunity from two main sources. One is prior infection: most people on Earth have had Covid-19 at least once, many multiple times.

Ziyad: The second source of immunity is vaccination. We are no longer immunologically naive. We are no longer encountering a virus that our immune system hasn't seen before. The immune system recognizes it and knows how to deal with it.

Ziyad: This time around, it handles it better and the body doesn't get as sick as during the first encounter.

Brent: If we went back and were to do it over again knowing what we know today, where did we get it right, and where did we get it wrong? For example, my own opinion: I was living in San Francisco at the time, and they closed down all the trails.

Brent: You couldn't go to the beach or on any of the trails—that feels like overkill knowing what we know today. I had a daughter in preschool; they masked all the preschoolers and held class outside or over Zoom. Masking toddlers might have been overkill, or not treating prior infection as equivalent to vaccination.

Brent: Where did we do too much, and where did we do too little? What's your assessment of how we handled it?

Ziyad: Broadly speaking, what we got right was accelerating vaccine development. Operation Warp Speed was a remarkable accomplishment in scientific and human history—developing a vaccine for a novel virus within a few short months.

Ziyad: By mid-December of 2020, in the same year the virus spread across the United States, people were receiving vaccines. That was a remarkable feat, and we definitely got that right.

Ziyad: Regarding lockdowns and pandemic restrictions, there wasn't always a careful understanding of the tradeoffs—instituting a measure while evaluating its repercussions on people's lives, economic development, education, and other crucial areas.

Ziyad: There wasn't always a balanced understanding of how policy impacted people's lives or striking the right balance. Overall, the biggest victory was the development of vaccines.

Brent: It does seem like developing vaccines so quickly was a Herculean effort. What is the difference between standard Covid symptoms and long Covid? Covid makes us sick for a period of time, which is normal and not called long Covid.

Brent: Then there's a period where symptoms linger past when they should. How do we define both?

Brent: What is a normal Covid experience versus when we say someone has long Covid?

Ziyad: Covid is primarily a respiratory infection initially. Generally, people experience fever, chills, cough, or fatigue. In most people, those symptoms resolve within a few days to a week.

Ziyad: If people continue to have persistent health problems more than 90 days after initial infection—such as ongoing fatigue, chest pain, or dizziness—you enter the realm of long Covid. These persistent symptoms long after initial infection are generally characterized by fatigue and brain fog.

Ziyad: Some people experience POTS (Postural Orthostatic Tachycardia Syndrome), getting dizzy with a rapid heart rate. These collective manifestations are referred to as long Covid.

Brent: So we draw the line at 90 days. A typical case of Covid might last one to two weeks, with symptoms tapering off over another couple of weeks.

Brent: At 90 days or longer, if symptoms persist, we start thinking about long Covid. What percentage of people who get Covid end up developing long Covid?

Ziyad: That percentage has changed over the course of the pandemic. Early estimates from March 2020 suggested about 10% of people who contracted Covid-19 developed long Covid. That percentage declined over the years.

Brent: 10%?

Ziyad: 10% of people infected initially developed long Covid, but that percentage has declined—driven largely by vaccination, reduced severity of infection, and the virus evolving to be less severe. Estimates from 2024 indicate about 3.5% of people who get infected may develop long Covid.

Ziyad: Although the risk of long Covid has declined due to viral changes and population immunity, people are still developing new cases of long Covid.

Ziyad: It hasn't disappeared. Even with a changing virus and increasing immunity, long Covid is still occurring.

Brent: The percentage of people who develop long Covid after infection has dropped from around 10% to roughly 3.5%.

Brent: How many people currently have long Covid?

Ziyad: We estimate that about 20 million Americans are suffering from significant long Covid today. When my group studied the global impact to understand its burden worldwide, we estimated about 400 million people globally.

Ziyad: That's about 20 million individuals in the US and 400 million globally.

Brent: 20 million people in the US today currently have long Covid, correct?

Ziyad: Correct.

Brent: That's a very high number. How long does it last? If symptoms persist at 90 days with fatigue and brain fog, how long can someone expect those symptoms to continue?

Ziyad: A small minority of patients recover after a few months. They experience long Covid initially, but eventually recover from brain fog and other manifestations.

Ziyad: However, a distinct subset of patients who developed long Covid in March 2020 still suffer from it years later. Others recover around the 2 to 3-year mark.

Ziyad: A substantial number of patients—20% to 30% depending on the study—have suffered from long Covid for several years.

Brent: That's brutal. Dealing with that for such a long period of time is hard to imagine. How do we diagnose long Covid? A common question is: if someone had Covid three months ago and feels foggy or tired now, how do we definitively connect that back and confirm it's long Covid?

Brent: How do we rule out just having a bad week, poor sleep, or dietary factors?

Ziyad: The collection of symptoms is fairly specific. When linked to an infection several weeks prior where the patient notes cognitive decline following the illness, it becomes clear.

Ziyad: POTS is also very characteristic and not something seen every day in general practice.

Ziyad: When a patient tracks their health following an acute infection, the onset of these symptoms is clear. The field needs to develop better biomarkers and imaging to quantify tissue damage and blood abnormalities, and significant research is underway to establish those parameters.

Ziyad: Listening to and believing the patient is key. Some dismissal of long Covid stems from our incomplete understanding of a new condition.

Ziyad: Historically, before seizures were understood as abnormal electrical activity in the brain, patients were called possessed or insane. We tend to psychologize illnesses we don't fully understand.

Ziyad: Instead of devoting resources to unlocking its mysteries, some people dismiss long Covid, similar to how seizures were dismissed centuries ago.

Ziyad: Once science identified abnormal electrical signals in the brain causing jerky movements, we understood it as epilepsy rather than madness.

Ziyad: Now that we understand the disease, we no longer dismiss those patients.

Brent: Is long Covid diagnosis trickier than seizures? With seizures, physical signs like eyes rolling back or shaking are obvious, even if historical attribution was wrong. With Covid, symptoms like brain fog or fatigue are less visually obvious than foaming at the mouth.

Brent: Without a definitive test, isn't diagnosis more complex, or are brain fog and tachycardia distinct enough to diagnose directly?

Brent: The eyes rolled back into the head and and shaking uncontrollably on the ground. So in the absence of a definitive test, isn't the diagnosis here a little bit trickier, or is it that I don't really understand? You know, brain fog is just really obvious. And this tachycardia that you're describing is really obvious. And so actually it's pretty straightforward to diagnose based on the same symptoms.

Brent: In the absence of that test.

Ziyad: The difference comes down to clinical training and knowledge. When seeing long Covid patients, the symptoms are distinct. A patient describes marked cognitive decline where they can no longer perform basic daily or professional tasks.

Ziyad: Cognitive performance can be measured using clinical tests and tracked over time across visits.

Ziyad: Tests exist for POTS and other parameters. Objective abnormalities are evident. The gap occurs when physicians haven't received training in medical school to identify these diagnostic criteria.

Ziyad: That is where the gap occurs.

Brent: How severe are the symptoms? Being unable to write an email sounds severe. How debilitating is long Covid across the spectrum from mild fatigue to severe impairment?

Brent: How do we characterize severity?

Ziyad: It's a spectrum. On one end, people experience mild cognitive symptoms or mild fatigue that don't impair daily activities, work, or family care.

Ziyad: On the other end, some patients are bedridden and cannot get out of bed due to severe dizziness and post-exertional malaise. A simple activity like walking the dog half a block can cause profound exhaustion.

Ziyad: Patients can experience a "crash" requiring two to three days of recovery. While most fall in an intermediate range, a minority suffer severe disability.

Ziyad: A minority of patients have very severe disease to the point of being disabled or bedridden.

Brent: What is Covid doing to the body to cause brain fog and other symptoms? What biological mechanisms drive this?

Ziyad: There are several key hypotheses. One is immune dysfunction: after initial infection, some patients develop autoantibodies that attack their own cells.

Ziyad: Autoantibodies can attack neurons in the brain and other organ systems, leading to disease. A second hypothesis is vascular dysfunction. Covid-19 doesn't stay confined to the lungs; it provokes inflammation in endothelial cells lining blood vessels throughout the body.

Ziyad: Every organ needs blood supply, and blood vessels are lined by endothelial cells. Inflammation in these cells (endotheliitis) can occur in Covid patients.

Ziyad: Endothelial inflammation can trigger complement activation and microclots, impairing blood flow. This impaired circulation can manifest as brain fog, kidney issues, or liver disease. A third major hypothesis is viral persistence: while most people clear the virus within two weeks, in some patients the immune system fails to fully clear it.

Ziyad: The persistent virus hides in tissue reservoirs or immune-privileged sites, provoking chronic inflammation that leads to ongoing disease.

Ziyad: So viral persistence is the third explanation.

Brent: Covid seems much more systemic than the flu. We think of it as a respiratory virus, but it impacts the entire body. Are we finding that Covid or long Covid increases the long-term risk for heart disease, diabetes, Alzheimer's, or cancer?

Brent: How should we view the relationship between Covid or long Covid and increased risk for chronic conditions?

Ziyad: The "R" in SARS-CoV-2 stands for respiratory, but that is somewhat of a misnomer. It is a systemic multi-system virus that can attack nearly every organ system in both its acute and long Covid phases.

Ziyad: What distinguishes Covid from other viruses is that it significantly raises the risk for heart disease, diabetes, GI issues, and neurodegenerative conditions like Alzheimer's and dementia to a much higher extent.

Ziyad: We should conceptualize repeat Covid infections as a distinct risk factor for cardiovascular disease, heart attacks, and strokes.

Ziyad: People need to view Covid-19 as an established cardiovascular risk factor in the data.

Brent: What distinguishes people who develop long Covid from those who don't? Does general health—sleep, diet, exercise—protect against it, or is susceptibility more random?

Brent: How do we understand who gets long Covid?

Ziyad: That remains an open scientific question. Some individuals experience multiple infections without developing long Covid, appearing relatively resilient.

Ziyad: We do not fully understand why some people develop long Covid even from a initial infection while others seem immune. Potential factors include genetic predisposition or immune system characteristics.

Ziyad: Prior exposure to other viruses, how the immune system manages acute infection, and the specific viral strain involved all play a role. Covid-19 has evolved through many variants.

Ziyad: Variants ranging from the ancestral strain to Delta and various Omicron subvariants carry distinct risks of triggering long Covid.

Ziyad: These combined variables drive the differences in individual outcomes.

Brent: Does vaccination status alter the likelihood of developing long Covid?

Ziyad: Vaccines reduce but do not eliminate the risk of long Covid. Multiple studies across the US, UK, Europe, and globally consistently demonstrate that vaccinated individuals have a lower risk of developing long Covid.

Ziyad: While vaccines do not completely eliminate the risk, they measurably lower it.

Brent: If someone contracts Covid, what steps can they take to minimize their risk of developing long Covid? Are there specific supplements or acute care strategies recommended?

Brent: Or do we lack sufficient data for specific recommendations?

Ziyad: Staying up to date on vaccination and reducing exposure risk in the first place are primary steps. Prevention remains better than treatment, though exposure cannot be entirely eliminated in daily life.

Ziyad: During acute infection, qualifying individuals—such as older adults or those with comorbidities—can use antivirals like Paxlovid, which studies suggest may lower long Covid risk.

Ziyad: I personally took Paxlovid when infected to help reduce my risk of long Covid. Research also suggests metformin taken during acute infection may reduce long Covid risk.

Ziyad: General supportive practices—rest, hydration, and allowing the immune system to fight off the virus quickly—are critical.

Ziyad: We advise seeking early clinical care if symptoms linger beyond a few months. Patients who seek early evaluation generally have better outcomes than those who wait years before consulting a doctor.

Ziyad: Seeking timely care from a primary physician for lingering brain fog, dizziness, or fatigue leads to better overall prognosis.

Brent: Vaccination, Paxlovid, early medical care, and metformin—which is interesting given its role in type 2 diabetes and anti-inflammatory properties. Do any pharmaceutical companies producing these treatments support your research or hold financial relationships with you?

Ziyad: No. My research is entirely supported by government funding.

Brent: Addressing potential skepticism is important, even if legitimate research collaborations exist. So your recommendations are strictly evidence-based.

Brent: How prevalent is skepticism within the medical community regarding long Covid as a distinct condition?

Brent: Is skepticism driven by public politicization around Covid or perceived ambiguity in diagnostic criteria? While the clinical criteria are defined, public perception might vary.

Brent: A problem?

Ziyad: Yes, skepticism is a challenge. Three primary factors contribute: first, the heavy politicization of the pandemic, leading some people to disengage from the topic.

Ziyad: Second, collective pandemic fatigue and trauma cause people to want to move past the topic. Third, a lack of training in the provider community creates gaps in care.

Ziyad: Because long Covid is a new medical condition not yet included in traditional medical school textbooks, many practicing physicians lack formal training on diagnostic criteria.

Ziyad: Busy clinicians managing heavy patient loads may feel unequipped to handle complex long Covid presentations without established protocols.

Ziyad: We must better support healthcare providers by equipping them with updated diagnostic criteria, guidelines, and resources. Clinicians need structured tools to manage new conditions effectively.

Ziyad: The broader societal politicization remains a significant obstacle in addressing the illness.

Brent: What is your current perspective on booster doses? Initially, my family prioritized getting vaccinated early, including my daughter. Over time, I became less certain about the ongoing necessity of boosters for everyone.

Brent: I haven't received recent boosters, nor has my nine-year-old. My younger children haven't received initial Covid vaccines, though I wonder what the evidence recommends.

Brent: What are current booster guidelines? Who benefits most—is it primarily high-risk populations, or does age and gender factor in? How should we evaluate vaccines for young children?

Ziyad: The clinical data remains clear. We evaluated this in a recent paper examining whether vaccines still provide measurable value given changes in viral strains and population immunity.

Ziyad: The findings indicate vaccines continue to add value, with a nuance: older adults and individuals with underlying health conditions derive the largest absolute benefit.

Ziyad: High-risk groups face the highest baseline risk for severe outcomes like hospitalization or mortality. While absolute benefit is lower in younger populations, it remains positive.

Ziyad: Discussions around vaccination should balance benefits against rare risks, such as myocarditis in young males or rare neurological events.

Ziyad: The health risks associated with Covid infection exceed the risks associated with vaccination. Overall, vaccines continue to offer net protection, with immunocompromised and older individuals benefiting most.

Ziyad: That population benefits most from vaccination.

Brent: Would you advise vaccinating a healthy young child or booster doses for school-aged children?

Ziyad: Based on available data, vaccine benefits outweigh risks across populations. However, individual decisions for children should involve informed discussions between parents, pediatricians, and families to determine the best approach.

Brent: So while net benefits favor vaccination, choosing not to vaccinate healthy young children for Covid specifically is a reasonable parental choice given their lower overall risk profile.

Brent: For a healthy child who is already vaccinated, opting against further boosters is a valid personal judgment.

Ziyad: It comes down to a careful judgment call. Beyond acute illness, long Covid affects pediatric populations as well. While lower in incidence, pediatric long Covid can significantly disrupt developmental milestones, school, and activities.

Ziyad: Observing children in pediatric long Covid clinics managing cognitive fog during critical developmental years highlights the condition's impact.

Ziyad: Because vaccination reduces long Covid risk, clinicians lean toward providing extra protection. Nevertheless, family values and medical advice shape final choices.

Ziyad: It warrants a shared decision-making discussion with a pediatrician.

Brent: Vaccinating healthy children strictly for acute Covid may seem optional given mild initial symptoms, but reducing the risk of debilitating long Covid provides a strong rationale for vaccination.

Brent: The primary value lies in protecting against potential long Covid complications rather than short-term symptoms alone.

Brent: Vaccination lowers that risk.

Ziyad: Vaccines reduce long Covid risk across age groups. Even with low baseline pediatric risk, avoiding long-term complications is a primary goal.

Brent: For your own healthcare, you receive annual boosters?

Ziyad: Yes. I prioritize reducing my overall risk of infection and long Covid.

Brent: Dr. Ziyad Al-Aly, thank you for joining us, sharing your insights, and for your research.

Ziyad: Thank you for having me. I truly enjoyed our conversation.