RECOVER’s tissue pathology (autopsy) study makes unique contributions to Long COVID research

What long-term effects does COVID-19 have on the body? Are these effects damaging? What parts of the body can be damaged, how long does that damage last, and which Long COVID symptoms may occur as a result of that damage? The RECOVER tissue pathology (autopsy) study will produce answers to these questions, and those answers could significantly enhance our ability to prevent and treat Long COVID.

In this study, researchers perform a detailed medical exam, called an autopsy, on people who die after having COVID-19. During the autopsy, researchers look at both the outside and inside of the body for signs of health problems. They also collect tissue samples, called biospecimens, during this process. Later, pathologists – scientists who specialize in studying fluids, tissues, or organs taken from the body to gain a better understanding of the causes, nature, and effects of a disease – can look at these biospecimens in greater detail and do tests to learn how COVID-19 affects the body.

To date, approximately 200 people with and without Long COVID have donated 17,000 biospecimens to the RECOVER Biorepository. This represents a remarkable contribution to science according to James Stone, MD, PhD, a leading researcher and Chair of the RECOVER Autopsy Cohort Coordinating Committee. “We have the opportunity to look at tissues throughout the body thanks to the people taking part in this study,” he explains. “Furthermore, we’re not really limited in which tissues we can look at. We can look at brain tissue, heart tissue – overall, more than 50 different tissue sites in the same patient.”

Even as this collection of biospecimens grows, RECOVER researchers are planning studies to investigate what may be one of the most common causes of Long COVID: viral persistence.

What is viral persistence?

Viruses can stay in the body even after a person has recovered from the initial (acute) illness that a virus can cause. This lingering virus can remain active or be inactive (dormant). The amount of time an active or dormant virus stays in the body could be related to whether someone develops long-lasting health problems. These health problems can include infection-associated chronic conditions (IACCs), a broad category that includes Long COVID, postural orthostatic tachycardia syndrome (POTS), and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Active viruses can continue to cause damage to organs like the heart, lungs, and brain. Both active and dormant viruses can cause the body’s immune system, which fights off infections, to not function properly. Dormant viruses can also reactivate later – either because of another infection or as part of their natural lifecycle – and begin causing damage.

Although there are likely many different causes of Long COVID, RECOVER researchers believe that viral persistence can help explain why some people experience fast heart rate, shortness of breath, upset stomach, and exhaustion (feeling very tired or lacking enough energy to participate in daily activities like going to work or school) months or even years after they had COVID.

RECOVER studies and findings about viral persistence

• RECOVER researchers have found parts of SARS-CoV-2, the virus that causes COVID, in the blood of people with Long COVID.
• RECOVER researchers have also found important differences in the immune systems of people with Long COVID compared to people without Long COVID. For example, people with Long COVID who took part in one study had lower levels of cortisol, a hormone that helps control the body’s response to stress and reduces inflammation, than people without Long COVID.
• The RECOVER-VITAL clinical trial is testing whether Paxlovid, a drug that can prevent SARS-CoV-2 from multiplying, can also improve Long COVID symptoms.

What will researchers learn about viral persistence from the tissue pathology (autopsy) study?

The RECOVER tissue pathology (autopsy) study is unique in its ability to answer three crucial questions about viral persistence.

1) Where does persistent SARS-CoV-2 virus remain in the body?

Because RECOVER researchers are collecting biospecimens from all over the body, tissue pathology studies should be able to pinpoint areas of the body that act as viral reservoirs. These viral reservoirs may be located in organs or cells that the immune system cannot reach, therefore giving a virus an opportunity to continue making copies of itself or pieces of itself (replicating). These pieces of a virus, often specific molecules called viral proteins, can spill out of a viral reservoir and enter a person’s bloodstream. “If the virus is actually hanging out in an organ and not just circulating in the blood,” Dr. Stone says, “tissue analyses should show us where. Tissue analyses should also help us understand whether the virus in those reservoirs is active or dormant.”

Ultimately, the various Long COVID symptoms experienced by different patients may be due to different viral reservoirs. Dr. Stone notes that “even if viral persistence is a factor, the resulting symptoms are likely not going to be the same for every patient.” For example, viral persistence in lung tissue could lead to very different symptoms than viral persistence in nerve tissue.

2) How long does persistent SARS-CoV-2 virus remain in the body?

The answer to this question depends in large part on what RECOVER learns about the location of viral reservoirs. Some cells, like neurons (nerve cells) and cardiac myocytes (heart muscle cells) have long lifespans. But other cells that SARS-CoV-2 can affect, like gastrointestinal mucosa (cells that line the inside of the stomach), are much more short-lived. According to Dr. Stone, answering questions about the specific cells harboring persistent virus could make “a big difference when deciding how long someone might need antiviral treatment for their symptoms.”

3) What changes in the body does persistent SARS-CoV-2 virus cause?

Persistent virus may affect each part of the body differently. Even more importantly, some changes the virus causes may be reversible while others are irreversible. “In some patients, some of their symptoms may be due to irreversible changes, like scar tissue,” explains Dr. Stone. “Trying to target those symptoms may not be as helpful as targeting symptoms that are due to reversible changes, like inflammation.”

Dr. Stone reports that his own team at Mass General Brigham is currently studying the damage SARS-CoV-2 can do to very small blood vessels in the heart. This damage may be a cause of Long COVID symptoms like chest pain and pounding heartbeat (palpitations) in some people.

“We want to know if viral persistence can cause Long COVID. If it can, we want to know where the virus remains in the body. We want to know which Long COVID symptoms are due to reversible changes that can be targeted with treatments to relieve those symptoms, and we want to use this information to design clinical trials that deliver positive results.”

– Dr. James Stone, Principal Investigator, Chair, RECOVER Autopsy Cohort Coordinating Committee

What’s next for the tissue pathology (autopsy) study?

“The main activity for the study, which we hope to be launching in the very near future, is called ‘Pathology of PASC,’” reveals Dr Stone. “We will be inviting specially trained pathologists from across the country to examine the RECOVER biospecimens. We hope experts in every different organ and body system, from the brain to the heart, lungs, and immune system, will help us understand how and why COVID-19 leads to Long COVID.”

Moreover, because the tissue pathology (autopsy) study collects high-quality biospecimens, it could inform Long COVID research for many years to come. “We’re processing the tissue and fluid samples we collect very quickly. In many cases, we’re freezing these samples rather than using preservatives on them. This should help maximize our ability to learn from them,” Dr. Stone adds. “As the clinical trials and other analyses are completed, they will often point us in directions by raising new questions. Those new questions can oftentimes best be answered by going back to the tissue to reexamine it.”

Learn how you or a family member can take part in the RECOVER tissue pathology (autopsy) study.