A new study may explain why some people who get COVID-19 never return to normal and instead experience new medical conditions like cardiovascular disease, clotting dysfunction, activation of latent viruses, diabetes mellitus, or what’s known as “long COVID” after SARS-CoV-2 infection.
Roughly 15 percent of people who get COVID-19 experience long COVID, a term used to define the long-term physical, cognitive, and mental health impairments that persist from weeks to months after a person recovers from COVID-19.
In a recent preprint study published on medRxiv, researchers conducted the first positron emission tomography (PET) imaging study of T cell activation in individuals who previously recovered from COVID-19 and found that SARS-CoV-2 infection may result in persistent T cell activation in a variety of body tissues for years following initial symptoms. Even in clinically mild cases of COVID-19, this phenomenon could explain the systemic changes observed in the immune system and in those with long COVID symptoms.
To carry out the study, researchers conducted whole-body PET scans of 24 participants who were previously infected with SARS-CoV-2 and recovered from acute infection at time points ranging from 27 to 910 days following COVID-19 symptom onset.
A PET scan is an imaging test that uses a radioactive drug called a tracer to assess the metabolic or biochemical function of tissues and organs and can reveal both normal and abnormal metabolic activity. The tracer is usually injected into the hand or vein in the arm and collects in areas of the body with higher levels of metabolic or biochemical activity, which can reveal the location of the disease.
Using a novel radiopharmaceutical agent that detects specific molecules associated with a type of white blood cell called T lymphocytes, researchers found uptake of the tracer was significantly higher in post-acute COVID-19 participants compared to pre-pandemic controls in the brain stem, spinal cord, bone marrow, nasopharyngeal and hilar lymphoid tissue, cardiopulmonary tissues, and gut wall. Among males and females, male participants tended to have higher uptake in the pharyngeal tonsils, rectal wall, and hilar lymphoid tissue compared to female participants.
Researchers specifically identified cellular SARS-CoV-2 RNA in the gut tissue of all participants with long COVID symptoms who underwent biopsy—in the absence of reinfection—ranging from 158 to 676 days following initial COVID-19 illness, suggesting that tissue viral persistence could be associated with long-term immunological concerns. Although the uptake of the tracer in some tissues appeared to decline with time, the levels still remained elevated compared to the control group of healthy pre-pandemic volunteers.
"These data significantly extend prior observations of a durable and dysfunctional cellular immune response to SARS-CoV-2 and suggest that SARS-CoV-2 infection could result in a new immunologic steady state in the years following COVID-19," the researchers wrote.
To determine the association between T cell activation and long COVID symptoms, researchers compared post-acute COVID-19 participants with and without long COVID symptoms at the time of PET imaging. Those with long COVID symptoms reported a median of 5.5 symptoms at the time of imaging. Findings showed a “modestly higher uptake” of the agent in the spinal cord, hilar lymph nodes, and colon/rectal wall in those with long COVID symptoms.
In participants with long COVID who reported five or more symptoms at the time of imaging, researchers observed higher levels of inflammatory markers, “including proteins involved in immune responses, chemokine signaling, inflammation responses, and nervous system development.” Compared to both pre-pandemic controls and those participants who had COVID-19 and completely recovered, people with long COVID showed higher T cell activation in the spinal cord and gut wall.
Although the researchers attribute their findings to SARS-CoV-2 infection, all but one participant had received at least one COVID-19 vaccination prior to PET imaging. To minimize the impact of vaccination on T cell activation, PET imaging was performed more than 60 days from any vaccine dose except in one participant who received a booster vaccine dose six days prior to imaging. Except for that one participant, people who had received a COVID-19 vaccine within four weeks of imaging were excluded. Researchers also grouped participants by receipt of a COVID-19 dose greater than or less than 180 days prior to PET imaging—although vaccinated participants would have undoubtedly been included in both groups.
The researchers said their study had several other limitations, including small sample size, limited correlative studies, evolving variants, rapid and inconsistent rollout of COVID-19 vaccines, which required them to shift their imaging protocols, using pre-pandemic individuals as controls, and the extreme difficulty of finding people who had never been infected with SARS-CoV-2.
"In summary, our results provide provocative evidence of long-term immune system activation in several specific tissues following SARS-CoV-2 infection, including in those experiencing Long COVID symptoms," the researchers concluded. "We identified that SARS-CoV-2 persistence is one potential driver of this ongoing activated immune state, and we show that SARS-CoV-2 RNA may persist in gut tissue for nearly 2 years after the initial infection."
