Long COVID involves activation of proinflammatory and immune exhaustion pathways

In this study, researchers used RECOVER data and blood samples to learn more about the biological mechanisms (changes in the body) that can lead to the development of Long COVID symptoms.

The researchers analyzed health information and blood samples collected between 2020 and 2021 from a group (cohort) of 142 people not taking part in RECOVER studies. This cohort included people who did and did not have COVID-19 as well as people experiencing symptoms of Long COVID. To ensure the accuracy (validate) their findings from the study of the 2020-2021 cohort, researchers compared them to findings from a different cohort that also included people without COVID-19, people with COVID-19, and people with Long COVID. The people in this cohort also took part in a RECOVER clinical trial between 2022 and 2024.  

Researchers performed multiple tests on blood samples collected from both cohorts and combined those analyses with health data collected from cohort members. The combined test results and health data suggest that Long COVID is associated with changes to the body’s immune system. Among people taking part in the study, the most important of these changes were chronic (long-lasting) inflammation and T cell exhaustion. While inflammation can indicate that the immune system is overreacting and even attacking healthy parts of the body, T cell exhaustion means the immune system has a reduced ability to fight off infections like SARS-CoV-2, the virus that causes COVID-19. Evidence of inflammation and T cell exhaustion appeared in multiple types of blood sample analysis data, including data about how individual immune cells behave and how a person’s body creates the proteins it needs to repair damage. Researchers also found that people who experienced inflammation during an initial (acute) SARS-CoV-2 infection were most likely to develop symptoms of Long COVID like pain, cough, brain fog, and fatigue.  

The findings suggest that the immune system may stay activated, and sometimes in a weakened state, for a long time after a person has had COVID. These findings are important because they could inform future studies on diagnosing and treating Long COVID.