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What is causing long COVID?

KU Medical Center is part of a national study to determine why some people have lingering health issues after contracting COVID-19.

Carroll Oliver sitting with a book in her lap
Carroll Oliver

Nearly three years in, the COVID-19 pandemic has slowly begun to ease in the United States. But deaths due to COVID, which were averaging more than 400 per week in late 2022, remain too high. At the same time, new COVID variants — specifically the omicron subvariants BQ.1 and BQ.1.1 — are not as responsive to treatments and vaccines. Meanwhile, another public health crisis is looming: the impact of “long COVID,” the condition attributed to people who suffer from persistent and potentially serious symptoms weeks or months after their COVID-19 illness has passed. These symptoms — including pain, headaches, fatigue, “brain fog,” shortness of breath, anxiety, depression, fever, cardiovascular problems, chronic cough and sleep problems — affect a striking number of people who have been infected by the SARS-CoV-2 virus. 

One of those people is Carroll Oliver, a community engagement specialist from Kansas City, Missouri. Despite being fully vaccinated and boosted — and wearing a mask religiously — Oliver, who just turned 60 years old, contracted COVID in January of 2022. She said her initial bout with COVID was relatively mild. She was tired but didn’t come down with any of the respiratory symptoms that many others experience. Oliver said she felt like she was well on the road to recovery, but about six weeks after coming down with COVID, she began to develop some troubling health issues. 

“I noticed my brain wasn’t really working right,” Oliver said. “I felt in a fog, I kept forgetting things, and I had trouble concentrating during meetings at work. I had recently lost my mother to Alzheimer’s disease, so I was terrified I might be having early-onset Alzheimer’s.” After conducting cognitive testing and undergoing an MRI and a magnetic resonance angiogram (MRA), Oliver’s doctors quickly ruled out Alzheimer’s. But the tests did show that there had been changes in her brain since contracting COVID.

In addition to the brain fog, Oliver said she began experiencing balance and gait problems and often found herself gasping for breath. That led to a slew of pulmonary tests, as well as weeks of physical therapy to help with her balance issues. Her doctor finally told her that she was most likely suffering from long COVID, although a definitive diagnosis is often difficult to make.

Three years into the pandemic, scientists still do not know how the virus triggers such a wide spectrum of symptoms that can persist months after the initial infection, why some of these symptoms show up in some patients but not in others or what exactly the risk factors are for developing them.

In a study that examined nearly 2 million patient records, the Center for Disease Control and Prevention found that one in five COVID survivors ages 18 to 64 and one in four ages 65 and older developed a persistent health problem that could be related to long COVID. If the findings prove accurate for the broader population, millions of people in the United States may have some form of the condition.

“We estimate that somewhere between 20% and 30% of people who've had an acute COVID-19 infection will develop symptoms of long COVID,” said Mario Castro, M.D., MPH, vice chair for clinical and translational research in the Department of Internal Medicine and a pulmonologist at The University of Kansas Health System “This is likely to be one of the top public health problems we face in the near future and probably for the next decade.” 

Beginning to Recover 

Mario Castro standing in a stairwell with arms crossed
Mario Castro, M.D., MPH

In February of 2022, Castro and his colleagues began enrolling their first participants in a multi-site clinical trial to understand how and why some adults develop “Post-Acute Sequelae [symptoms] of SARS-CoV-2 infection” (PASC), which includes long COVID, and others do not. The trial, coordinated by New York University Langone Health, is sponsored by the National Institutes of Health and is part of the NIH Researching COVID to Enhance Recovery (RECOVER) Initiative.

The $1.15 billion taxpayer-funded study aims to enroll nearly 40,000 people nationwide by the end of 2022, including 17,000 adults and 20,000 children. It will follow those participants over four years, comparing people who have had COVID to those who’ve never had it, with the goal of identifying all the long-term symptoms and finding out how the virus might be causing them.

KU Medical Center received a $1.1 million grant to participate in the RECOVER study as part of the IDeA States Consortium for Clinical Research (ISCORE), a network of 11 states that helps ensure diversity in medical research funding. 

“We were chosen purposely because we have quite a bit of diversity within ISCORE, including Native Americans, African Americans, Hawaiians, Pacific Islanders and rural populations,” Castro said. “That made our network unique in that regard.” 

Working with their clinical partners at The University of Kansas Health System, KU Medical Center aims to enroll more than 200 participants. Participants will include people who have not contracted COVID-19 as well as those who have, and people with PASC symptoms as well as those without. The study will follow the participants for up to four years. 

"This is likely to be one of the top public health problems we face in the near future and probably for the next decade."

Social and Biological Factors 

Because it is not yet known who is at a higher risk for long COVID, it is hard for physicians to know how to treat this patient group. Some people with long COVID — like Carroll Oliver — were not even that sick when they originally contracted COVID. Some have prolonged symptoms, while others develop new symptoms after getting over an acute case of COVID-19. Moreover, the severity and array of PASC symptoms varies widely among patients. 

“We’d like to understand better what are the risk factors that lead to not just CoV-2 infection, but the development of PASC. We don't really have a good understanding of that at this point,” Castro said. “Social determinants may also lead to PASC, such as having poor access to care or not being able to get prompt treatment, and we need to understand these better.” 

There are also, of course, unique aspects of the virus itself that likely lead to the symptoms, Castro said. He points to work led by Navneet Dhillon, Ph.D., professor and director of pulmonary research at KU School of Medicine, as one potential answer to the biological puzzle of long COVID. Dhillon has conducted research on patients hospitalized with COVID-19 and found that extracellular vesicles — membrane-bound nanosized particles circulating in patients — can be used as non-invasive biomarkers of the inflammatory response and disease severity of COVID-19. The particles can also damage endothelial cells, which line the blood vessels. The vascular injury leads to organ damage, such as to the heart and lungs, in some COVID-19 patients. 

Dhillon and her colleagues believe this phenomenon could also lead to PASC. 

“We are hypothesizing that maybe there's a sustained injury that continues, that leads to this long-haul disease,” she said. 

A Benefit for Study Participants and for Science 

Everyone participating in the study, including the people who have never been exposed to the SARS-CoV-2 virus, will have a basic physical exam and blood work and complete a health questionnaire. Depending on their symptoms and infection status, they may undergo more detailed testing such as chest CT scan, heart MRI, electromyography as well as testing of nerve function. People entering the study believing that they have never had been infected with SARS-CoV-2 will have an antibody test to confirm that they have not been exposed. 

Those tests, conducted by KU Medical Center in partnership with The University of Kansas Health System, may help study participants and their physicians better understand problems that are related to COVID-19. 

The results of the study will be important in understanding the body’s long-term reaction to COVID-19. 

“The RECOVER study is extremely beneficial for anyone with PASC symptoms, as the main aim of the study is to better understand symptoms post COVID-19 infection,” said Adam Ruff, the clinical research coordinator for RECOVER at KU Medical Center. “The study is open to enrollment for individuals at least 18 years of age who have previously had COVID-19, are currently positive with COVID-19 and individuals that have never tested positive or had symptoms of COVID-19. 

As Ruff has begun to enroll participants, he's noticed a wide range in illness severity among candidates. 

“I've talked with many of them that have extremely severe symptoms and are trying to get into the study as soon as possible. I've also had conversations with individuals who have mild to moderate symptoms,” he said. “So, for scientific integrity and research purposes, it's important that we enroll as many people and collect as much data as possible, even on individuals who aren't experiencing a lot of symptoms.” 

The study’s conclusions could play a pivotal role in developing diagnostic tests and finding treatments for patients who remain sick months after contracting COVID-19. If scientists can produce clinical definitions of the various long-term illnesses associated with the virus, patients will stand on firmer ground when trying to convince health insurers to cover their treatments and getting disability claims approved. 

“Our hope is that at the end of the day, we will be able to give clinicians a strategy to manage these patients,” Castro said. 

Carroll Oliver is also hoping she can get some answers for the health problems she has been experiencing since getting COVID. In the meantime, because of her persistent health issues, she has had to leave her job at Humana and is in the process of going on long-term disability. 

“My doctor told me I might not ever fully recover from COVID and could be dealing with my symptoms for the rest of my life, which is really depressing,” Oliver said. “I’m hoping with more research, scientists will be able to discover what is causing people like me to have long-lasting health issues after COVID — and can come up with better ways for us to live with long COVID.”


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