Understanding Long COVID

Some people who have been infected with the virus that causes COVID-19 can experience new or persistent changes to their health following a COVID-19 illness, which is scientifically known as post-acute sequelae of COVID-19 (PASC) and commonly referred to as long COVID. Patients with long COVID also often refer to themselves as “long-haulers.”

Long COVID is broadly defined as signs, symptoms, and conditions that continue or develop after acute COVID-19, the initial COVID-19 infection.

“Post-viral illnesses are not new,” explains Dr. Brode. “We’ve seen fatigue and neurologic symptoms after previous pandemics, such as the Spanish Flu or even the original SARS (severe acute respiratory syndrome) virus. When we’re talking about long COVID, it’s a question of what is a virus we’ve never seen on this scale in modern times versus what is the COVID-19 virus cause in particular, and long COVID is probably a confluence of both of those phenomenon.”

Long COVID

“Right now, there’s not a consensus definition or even a diagnostic test that can diagnose long COVID, but most experts agree that if symptoms began after COVID-19 infection, there’s not an alternate medical explanation for the symptoms, and they’re lasting more than 4 weeks, that it probably is long COVID,” explains Dr. Brode.

Acute COVID

“What we do know, though,” adds Dr. Brode, “is that the active initial COVID-19 infection can last up to four weeks. People experience rapid healing during that time. It slows between 4 and 12 weeks and then after that, the healing plateaus. So usually at about 12 weeks, the symptoms that are still there are the ones that are most likely to persist, and that’s when most experts are going to say long COVID starts, at 12 weeks after the initial infection.”

Framework for Long COVID

“The framework of understanding long COVID can be overwhelming,” shares Dr. Brode. “Some research has said there are more than 50 symptoms; other research, more than 100. One paper even identified 203 symptoms from long COVID.”

Categories of long COVID symptoms include:

1. Detectable organ or tissue damage
2. New chronic illnesses after COVID-19 illness
3. Mysterious new symptoms

“Detectable organ or tissue damage, such as lung scarring, is almost exclusively in patients who were hospitalized or had severe illness that required them to be in the hospital and getting oxygen,” explains Dr. Brode. “There is research to suggest that people are more likely to develop new chronic illnesses, such as diabetes, blood clots, fatty liver disease, or stroke following a COVID-19 illness than not.”

“For those two things,” continues Dr. Brode, “having detectable organ damage from a severe illness or developing a new condition, most people don’t think about those as long COVID because those are detectable problems that we have evidence-based treatments for. Most people would consider that a post-COVID-19 condition.”

“Long COVID, on the other hand, is more of this syndrome of symptoms in the absence of an identifiable problem on a lab test, and this would be the mysterious illness or strange symptoms people are developing, which we more consider to be long COVID,” notes Dr. Brode

Mysterious new symptoms include:

1. Post-viral symptoms
2. Neurologic/inflammation symptoms
3. Fatigue, brain fog, and post-exertional malaise

“Post-viral symptoms include cough, shortness of breath, muscle pain, joint pain, or headaches; it’s almost as if people got this viral flu-like illness and it never went away and those symptoms never got better,” explains Dr. Brode.

“Neurologic or inflammation symptoms really show up most prominently in neurologic problems of the autonomic nervous system. That’s the automatic part of the nervous system, the part that controls heart rate, blood pressure, gut movement, and temperature regulation,” adds Dr. Brode. “We’re really seeing that with long COVID, there can be a lot of new neurologic symptoms following the COVID infection.”

“Fatigue, brain fog, and post-exertional malaise, a medical term that just describes the phenomenon of if you do an activity that normally would not be tiring, it just wears you out and it makes all your problems worse, is almost universal in people with long COVID,” continues Dr. Brode.

“It has been my observation that those three things are interrelated,” shares Dr. Brode. “The fatigue is real, and that’s the most common symptom of long COVID. The brain fog is really deficits of concentration, attention, and processing, so on formal testing, most people can compensate and do quite well. But in the real world, it really rears its head. Maybe the word is on the tip of your tongue, or you walk into the living room and can’t remember why or just have a lot of trouble focusing. It seems it’s very clearly related to the fatigue, and that makes sense.

“The brain is the most metabolically active organ in the body, so that uses and can drain your energy just as much as doing physical exercise,” explains Dr. Brode. “And the terrible thing about long COVID, if you drain that energy too much, you hit a wall and you pay for it. You experience the post-exertional malaise, and it makes all your symptoms worse.”

“For long COVID, there’s not a discrete definition,” notes Dr. Brode. “People can experience a mix and match of symptoms from organ damage to developing new illnesses, such as diabetes, or experiencing these mysterious symptoms. It’s not always perfect, but I think those categories of symptoms are what most people are thinking about when they think long COVID.”

“The Centers for Disease Control and Prevention (CDC) estimates that 15% of the total US population has had long COVID at one point, which makes up almost 40 million Americans,” shares Dr. Brode. “The CDC also estimates that 6% of people still have long COVID, which makes up 15 million Americans. As of now, the CDC estimates 5 million people are out of the workforce because long COVID can be disabling and that there is going to be half a trillion dollars of extra medical costs to our society.”

“A lot of people are going through this, and this is going to have a lot of repercussions from the pandemic that are going to stay with us,” adds Dr. Brode.

“While we don’t know exactly who is most at risk,” notes Dr. Brode, “there are two main categories.”

People who are more likely to develop long COVID include:

1. People most at risk of severe COVID-19
2. People with autoimmune conditions or low-level autoimmunity

“The first category is pretty obvious in that the people who get the sickest and are at the highest risk of getting sick from COVID-19 are more likely to develop long COVID,” shares Dr. Brode. “This includes people who may be overweight, have diabetes, or are elderly. They are the most risk at for being hospitalized and experiencing those lingering symptoms.”

“The next category is a little less obvious,” explains Dr. Brode, “in which I consider that of people’s underlying immune system. People who have autoimmune conditions or some low-level autoimmunity, even if they don’t have a diagnosed autoimmune condition, seem predisposed to getting long COVID. This includes people with connective tissue disorders and asthma.

“Within that,” continues Dr. Brode, “women seem to be getting long COVID more than men. Once again, women are more predisposed to developing autoimmune disorders than men, so there does seem like there may be a connection there.”

“Lastly, and I think this is an area of important research, is that people who have reactivation of viruses in the body may be more predisposed to developing long COVID,” adds Dr. Brode. “The big example is Epstein-Barr virus (EBV). It’s the virus that causes infectious mononucleosis (mono). Some research shows that during the active COVID-19 infection, if that gets reactivated and loose in the body, those people are more likely to develop long COVID symptoms.”

“Although, it is important to note that when people are measured months later, usually the virus is out of their blood, so it’s unclear whether these viruses, such as EBV, are directly causing the symptoms or if they are just more part of the problems of the immune system response and inflammation from having the infection,” shares Dr. Brode.

“As of right now, we don’t know for sure,” says Dr. Brode. “There is no diagnostic test or specific set of symptoms that diagnose long COVID. When we can send a blood test to the lab to diagnose it and know the mechanism, that is going to be the medical breakthrough where someone is going to win someone a Nobel Prize. But right now, we don’t have it.”

“Presently, the main theory of long COVID is that it is caused by dysfunction of the immune system,” explains Dr. Brode. “The immune system protects the body from threats, bacteria, and viruses, but when it is over activated, it can start to cause problems such as inflammation or attack the body itself. Within that, there are some theories that there are viral fragments in the body that could be leading to that chronic inflammation, that it induces autoimmunity and the body attacks itself.”

“Other theories include problems with the vascular microclotting and problems or blood flow throughout the body or signaling within the nervous system,” continues Dr. Brode. “There is some new and emerging research that actually may say all of those things are happening. We don’t fully understand the mechanism.”

“Some research suggests that these viral fragments are causing chronic inflammation, which decreases serotonin and leads to problems of the neurologic signaling and even these micro clots, although that’s preliminary research that’s going to have to be validated in larger populations despite not having the exact mechanism figured out,” notes Dr. Brode.

“There are two things in the research that really stand out to me,” shares Dr. Brode.

Key takeaways from research into long COVID pathology include:

1. Neurologic inflammation
2. Poor exercise tolerance and oxygen use

“The first is that there is clearly neurologic inflammation occurring,” explains Dr. Brode. “What we’re seeing is that in some research, the part of the brain that is supposed to be keeping inflammation out actually gets activated, which is decreasing blood flow to the part of the brain that controls concentration, attention processing, and even the memory portions of the brain.”

“A lot of patients described they’re in this sort of fight or flight response,” observes Dr. Brode. “They’re more irritable than they have been. They have less reserve or are anxious in a way that they’ve never been before prior to the infection.”

“While most people experience the inflammation on the brain, a subset of patients can also experience it peripherally on the small nerves of their body,” adds Dr. Brode. “Those, once again, are the autonomic nerves that control heart rate, blood pressure, and temperature regulation. Some studies show that those near nerves can be damaged or are not working properly with long COVID.”

“The next category of research looks at exercise testing,” says Dr. Brode. “They take young, healthy people who now have long COVID and put them on a treadmill to see how they do.”

“Unfortunately, people with long COVID don’t do well exercising on a treadmill, but it’s for a very specific reason,” continues Dr. Brode. “As they start to move, their heart pumps the blood to their lungs to put oxygen in the blood, but for some reason, the blood returns to the heart full of oxygen that the body never used. But why is that?”

“Some research suggests that it’s a problem of cell metabolism,” notes Dr. Brode. “The body has to turn oxygen into energy. Other research suggests it may be a problem of blood flow. The body has got to get the blood flow to the right place at the right time and extract that oxygen efficiently to be able to use it for energy.”

“Like all things, probably a combination of both are happening. What we see with people on the treadmill is that as they start to exercise, they start to build an energy deficit because they’re not using that oxygen, and that tells the brain fix it,” says Dr. Brode. “And how does the brain fix it? Their heart rate goes up. They start breathing faster. They start to feel terrible in their chest and short of breath. But there’s nothing wrong with the heart or lungs. It’s just the body trying to deliver more oxygen and compensate for what is fundamentally an energy problem.”

“On these same tests, people don’t do well on the treadmill on day one, but if we bring them back the next day and try again, they do terrible,” shares Dr. Brode. “They have post-exertional malaise, and they have less exercise capacity after they build that deficit.”

At UT Health Austin, we focus on you, the whole patient, making sure that you have the support you need throughout your care. Our goal is to help patients recover from the lasting effects of COVID-19 through rehabilitation and other therapies designed to restore their function and quality of life.

“My first step is always to believe the patient,” says Dr. Brode. “Long COVID is absolutely a real illness affecting millions of Americans. It’s important to recognize that because it seems to be affecting women and women of color more than other people, and this group in particular is a group that doctors in the medical community have diminished in terms of their symptoms or disbelieved historically.”

“It’s important to be humble, even though we can’t explain it,” adds Dr. Brode. “This is an illness that is real, it’s affecting millions of people, and we just listen to the patients.”

“Next is that we really need to make sure that there are no other medical problems causing this condition,” continues Dr. Brode. “Heart disease, diabetes, and thyroid problems are common in the general population and can overlap with a lot of these symptoms. So, it’s important to make sure those things aren’t causing the problems, or if you have those problems, that they are well-managed and not contributing.”

“After that, is screening for mental health symptoms,” adds Dr. Brode. “I would argue that anxiety is part of the neuroinflammatory response of long COVID and depression is just part of being alive over the last three years. However, whether it is physiologic from the virus or simply dealing with a chronic and disabling disease without dealing with the mental health symptoms, we’re not going to have a foundation for recovery. It also weaves its way into people’s social lives and their financial needs. Once again, this can be a disabling illness, and if people are worried about losing their housing or losing their job and we’re not caring for those needs, they’re not going to have any foundation to build a recovery on.”

“Lastly, I do want to offer some good news,” notes Dr. Brode. “The statistics show that most people are getting better. According to the CDC, we went from 15% of people who have had long COVID to 6% who still have it. That suggests that 60% of people have gotten better. Most of that healing, in my experience, happens within the first year or year and a half. Even for the people who don’t fully recover within that timeframe, they are certainly getting better.”

“Time is a healer for most people as well as really managing long COVID symptoms by managing that energy and not hitting that wall of post-exertional malaise,” adds Dr. Brode. “Doing some intentional rehabilitation or symptomatic treatment can also be beneficial at managing the symptoms.”

“While researchers around the world are trying to find the one curative treatment, the research is preliminary,” shares Dr. Brode. “However, I think we’re making progress, and I really am seeing a lot of patients get better.”