Long COVID not caused by immune inflammatory response

Long COVID is not caused by an immune inflammatory reaction to COVID-19, according to new research led by the University of Bristol. Indeed, emerging data demonstrates that immune activation may persist for months after COVID-19. Results from the new study have been published in the journal eLife.

“Long COVID occurs in one out of 10 COVID-19 cases, but we still don’t understand what causes it,” said Bristol’s Dr Laura Rivino, senior author on the study. “Several theories proposed include whether it might be triggered by an inflammatory immune response towards the virus that is still persisting in our body, sending our immune system into overdrive, or the reactivation of latent viruses such as human cytomegalovirus (CMV) and Epstein–Barr virus (EBV).”

Seeking to investigate whether persistent immune activation and ongoing inflammation response could be the underlying cause of long COVID, the Bristol team collected and analysed immune responses in blood samples from 63 patients hospitalised with mild, moderate or severe COVID-19 at the start of the pandemic and before vaccines were available. The team then tested patients’ immune responses at three months and again at eight and 12 months post hospital admission. Of these patients, 79% (82%, 75% and 86% of mild, moderate and severe patients, respectively) reported at least one ongoing symptom, with breathlessness and excessive fatigue being the most common.

The team found patients’ immune responses at three months with severe symptoms displayed significant dysfunction in their T-cell profiles, indicating that inflammation may persist for months even after they have recovered from the virus. But even in severe cases, inflammation in these patients resolved in time. At 12 months, both the immune profiles and inflammatory levels of patients with severe disease were similar to those of mild and moderate patients.

Patients with severe COVID-19 were found to display a higher number of long COVID symptoms compared to mild and moderate patients. However, further analysis by the team revealed no direct association between long COVID symptoms and immune inflammatory responses, for the markers that were measured, in any of the patients after adjusting for age, sex and disease severity.

Importantly, there was no rapid increase in immune cells targeting SARS-CoV-2 at three months, but T cells targeting persistent and dormant CMV — a common virus that is usually harmless but can stay in your body for life once infected with it — did show an increase at low levels. This indicates that the prolonged T-cell activation observed at three months in severe patients may not be driven by SARS-CoV-2 but instead may be ‘bystander driven’, ie, driven by cytokines.

“Our findings suggest that prolonged immune activation and long COVID may correlate independently with severe COVID-19,” Rivino said. “Larger studies should be conducted looking at both a larger number of patients, including if possible vaccinated and non-vaccinated COVID-19 patients, and measuring a larger range of markers and cytokines.

“Understanding whether inflammation and immune activation associate with long COVID would allow us to understand whether targeting these factors may be a useful therapy for this debilitating condition.”

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