COVID-19 symptoms that haven’t gone away? You might have long COVID.

Five years after the COVID-19 virus swept across the globe, many people have already experienced and recovered from an infection. However, about 6% of people who get COVID never fully recover. They may have symptoms for three months or several years after getting the virus. This is called long COVID.

Long COVID can show up in many different symptoms, but two main areas of the body where it can continue to affect people is in the brain and the lungs.

“Many of our patients can trace their symptoms back to starting when they had COVID,” said Dr. Homer Twigg, a pulmonary critical care physician at IU Health. “They may come into the doctor’s office with a health complaint, but don’t initially tie it to having COVID. But when you talk to them about their infections they say, ‘I haven’t been right since I had COVID.’ The symptoms just never go away.”

“These patients might feel better for a couple weeks there or here, but they’re never quite over COVID,” added Dr. Sophia Wang, a geriatric psychiatrist specializing in Alzheimer’s disease. “These patients can’t do things the same way they used to, and they can feel very frustrated.”

Why do some people have long COVID?

Doctors think the first couple waves of COVID-19 infections were very potent, and some people simply couldn’t fully clear the virus from their systems. This is especially true for people with compromised immune systems. Long COVID describes how an immune system continues to react to leftover virus for months–and even years–after infection.

“We began doing studies looking for proteins or virus RNA in these patients long after COVID, and low and behold, it was there. You could still see evidence of the protein and RNA in the lung two or three years after the patient had a severe infection,” Dr. Twigg said. “We think this is leftover virus is driving their immune systems to respond, which leads to the inflammation that’s causing these other diseases.”

Unlike viruses such as herpes, which can lay latent in the body and then reactivate, COVID infections do not disappear and reappear. So why do pieces of it remain years after the initial infection?

“We’re looking to see if the COVID virus is protected within tiny particles that bud off of cells extracellular vesicles, or EVs,” Dr. Twigg said. “We’ve isolated EVs from the lung and blood of these patients with long COVID, and this is where the virus seems to stay, in this protected environment.”

Long COVID symptoms in the lungs

As an upper respiratory virus, COVID-19 is naturally headed for the lungs. While some people recover from the infection with mild symptoms, long COVID can leave lasting effects in the lungs for months and years to come.

Dr. Twigg runs a basic science laboratory at the IU School of Medicine, where he has a National Institutes of Health grant to study long COVID in the lungs. He suspects that a lot of cases of long COVID—whether it’s in the heart, lungs, brain or muscle—is related to this immune system response to leftover virus in the body. In the lungs, long COVID symptoms may include:

• Shortness of breath
• Persistent cough
• Infiltrates, or white spots, that appear on x-rays of the lungs

Dr. Twigg is seeing two types of lung diseases appearing because of long COVID: pulmonary fibrosis and cryptogenic organizing pneumonia, or COP. These diseases appear like they would in any other patient, but long COVID patients can tie their symptoms back to their initial infection. These patients are often immunosuppressed people, such as those on post-transplant medications or taking steroids for conditions like rheumatoid arthritis.

For long COVID in the lungs, early diagnosis is important for understanding treatment options and prognosis.

“When patients show up with symptoms and these infiltrates on x-rays, we’ll perform a bronchoscopy to look in the lungs and measure the type of inflammation there to figure out what’s going on,” Dr. Twigg said. “This is very important because if it’s pulmonary fibrosis, this is a difficult diagnosis; it can lead to death in five years or so. COP, however, is imminently treatable with steroids. So, it’s important to figure out exactly what the patient has.”

Sometimes the abnormalities seen on x-ray turn out to be just scar tissue. In this case, the bronchoscopy shows no signs of inflammation, and no further testing is necessary.

Long COVID symptoms in the brain

Whereas long COVD in the lungs has a clear and solid line from symptom and disease to treatment, it’s more of a dotted line in neurology, where long COVID in the brain and its treatments are still being understood.

There are a few ways that long COVID shows up in neurological symptoms:

• Brain fog
• Slower reaction times
• Difficulty concentrating

Brain fog is one common complaint in those who has long COVID. However, this phenomena of having “brain fog” after viral infections (which is often accompanied by fatigue after physical activity) is not new. This kind of fatigue wasn’t always taken seriously before the pandemic, but Dr. Wang says it’s been a common symptom of post-COVID infection. Although the reasons are not understood, the immune system is likely playing an important role in these long COVID symptoms. Although there is no cure for “brain fog,” there is growing evidence for neurocognitive rehabilitation playing a role.

Another group of people experiencing long COVID symptoms in the brain are those who were hospitalized in the intensive care unit with severe cases of COVID. These patients tend to be older, with other health issues when they got sick and were probably intubated on a ventilator. After all this, the COVID infection caused brain inflammation that can lead to difficulty multitasking, processing multiple lines of information or complex thinking.

“In the first couple waves of COVID, we saw very high numbers of patients who needed to be on oxygen support, whether it was a ventilator or high flow oxygen. There was also an increased risk of strokes after COVID-19 infection,” Dr. Wang said. “There appears to be something about COVID that causes a significant ramp up of vascular inflammation.”

The third major concern about the long-term effects of COVID-19 is whether this infection may increase the risk of cognitive decline. One area of research is whether people already at higher risk for dementia who were infected by COVID could have faster cognitive decline. Dr. Wang says there’s a growing amount of research data suggesting that viruses play an important role in the development of Alzheimer’s disease and other types of dementias. And there’s still more to discover about how it all works.

“These people probably don’t see themselves as having long COVID, but I suspect this may turn out to be one of the largest groups, after we’ve had time to study them,” Dr. Wang said. “I think we’ll find that in 10 years from now, we’ll look back and see the effects of COVID as one of many factors that pushed these patients in the wrong direction.”

Studying long COVID

There’s still a lot to learn about how long COVID works throughout the body, both now and in the future. Dr. Twigg has an ongoing study of long COVID to better understand the long-term effects of the disease on the lungs. He continues to look for people with persistent breathing troubles after COVID as well as healthy people he can study as control patients. Dr. Twigg says long COVID has taught us a lot about how people get disease through virus leftovers.

“I actually think this is now a model for why people get pulmonary fibrosis and other lung disease,” Dr. Twigg said. “I suspect when people get viruses, a lot of times all the pieces of the virus are not cleared, and this predisposes you to another disease.”

Dr. Wang adds that it’s important to remember inflammation can come in waves, so even if a patient has had COVID (or multiple strains of the virus), another wave can cause new issues.

“We can’t eliminate the possibility that another viral infection could rev up these people’s inflammation,” Dr. Wang said. “Inflammation isn’t a straight up or down – it comes in waves and phases. What we need to better understand is how these waves could cause long-term cognitive changes.”

One key question that needs further study is understanding the long-term effects of vaccination.

“There is some evidence from large dataset analyses that vaccinations for the flu and pneumonia may protect against Alzheimer’s disease, but what about other viruses?”
she said. “We really to understand how the immune system interacts with the brain to affect the risk of Alzheimer’s disease.”

If you feel you have long COVID symptoms, speak with your doctor about what you’re experiencing and what symptoms you may have developed since you were infected with this virus.