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Study Links Long COVID to Lasting Inflammation and Immune Exhaustion

A study published in Nature Immunology examined immune responses in people with long COVID and found evidence of sustained inflammation and immune exhaustion that can persist for months after initial infection. The researchers analyzed immune, transcriptomic, and proteomic data from 142 participants enrolled between 2020 and 2021, including individuals with long COVID, people who recovered fully, acutely infected patients, and uninfected controls.

Compared with recovered individuals, those with long COVID showed persistent activation of inflammatory immune pathways more than 180 days after infection. These included IL-6 signaling, JAK–STAT signaling, complement activation, and metabolic pathways linked to chronic inflammation. At the same time, markers of T cell activation were reduced, while signatures of T cell exhaustion were increased, suggesting that prolonged immune stimulation may impair normal immune function.

Notably, the researchers did not find evidence of ongoing viral replication in people with long COVID, indicating that persistent symptoms are more likely driven by immune dysregulation rather than lingering infection.

The same immune patterns were confirmed in an independent validation cohort recruited between 2023 and 2024.

The study also found that inflammatory responses during the acute phase of COVID-19 were predictive of who later developed long COVID.

Elevated inflammatory and JAK–STAT–related signaling early in infection was strongly associated with long-term symptoms, highlighting the potential value of early immune biomarkers.

Based on these findings, the authors suggest that targeting inflammatory pathways may offer new treatment approaches.

A clinical trial has already been initiated to evaluate the JAK1 inhibitor abrocitinib as a potential therapy for long COVID.

Citation

Aid, M., Boero-Teyssier, V., McMahan, K. et al. Long COVID involves activation of proinflammatory and immune exhaustion pathways. Nat Immunol (2025). https://doi.org/10.1038/s41590-025-02353-x