“Long COVID” Caused by Hidden Viral Reservoirs

Surviving a COVID-19 infection is only half the battle. Approximately 20-30% of people who contract COVID-19 develop post-acute sequelae of COVID-19 (PASC), commonly called “long COVID.”

Common symptoms of long COVID include fatigue, brain fog, shortness of breath, cough, chest pain, heart palpitations, headache, insomnia, and loss of taste or smell. These and other long COVID symptoms can be debilitating, with an estimated 1 million Americans out of work due to long COVID.

A recent study, published in PLOS Pathogens, compared the frequencies of COVID-19-specific T cells and inflammatory markers with lung function in patients who had either pulmonary PASC or resolved COVID-19.

“The persistence of high numbers of virus-specific T cells in individuals with long COVID suggests that there may be hidden viral reservoirs that are maintaining and leading to long-term symptoms,” said Brent Palmer, PhD, the study’s senior author and an associate professor of allergy and clinical immunology at the University of Colorado School of Medicine.

“Current treatments for long COVID, out of necessity, are focused on addressing specific symptoms and not the root cause of the illness. This evidence points toward the reservoirs as a significant factor causing long COVID, which can guide future treatments.”

Palmer and fellow investigators found that patients who suffered from long COVID had virus-specific T cell levels that were more than 100 times higher than in patients who made a full recovery. The patients with PASC had frequencies of IFN-γ- and TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells in peripheral blood that were 6-105 times higher.

In the long COVID patients, higher levels of SARS-CoV-2 T cells were correlated with higher levels of inflammation, indicating T cells could be driving these and other symptoms. The investigators concluded that the elevated frequencies of SARS-CoV-2 T cells in long COVID sufferers are associated with increased systemic inflammation and decreased lung function.

This study is the first to determine T cells specific to COVID-19 may affect lung function, causing long COVID. The findings may shift COVID-19 treatment recommendations, leading to a prioritization of vaccines and antivirals that target long COVID symptoms and clear the virus.

“Our findings hope to help change treatment focus to therapies that improve viral clearance,” Plamer explained. “For example, antiviral medications like Paxlovid could help reduce symptoms in those burdened by long COVID, helping to clear the virus out of their system and get them back to a more normal life.”

Palmer and his team applied for a National Institutes of Health (NIH) grant to continue this long COVID research. If approved, they would investigate washing T cells out of the lungs with a noninvasive procedure, enabling them to compare the cells of patients with and without long COVID.