Cross-sectional blood analysis finds exploratory immune-marker differences in long COVID

The investigators described both findings as exploratory and marginally significant, rather than as validated diagnostic biomarkers. The study examined whether cytokines, chemokines and growth factors in blood differed among people with long COVID, people in acute infection, spontaneous resolvers and participants who reported no known SARS-CoV-2 infection. Researchers collected venous blood samples from 127 participants and used Luminex assays to profile the concentrations of multiple signaling proteins.

The four groups comprised 63 people with confirmed long COVID, 22 with acute infection within three months, 21 spontaneous resolvers and 21 who reported no knowledge of infection. Long COVID participants were further classified by post-COVID-19 functional status. Nine had negligible limitations, 20 had mild limitations, 24 had moderate limitations and 10 had severe limitations.

Its median concentration in the overall long COVID group was 58 pg/mL, with an interquartile range of 49 pg/mL, compared with 45 pg/mL and an interquartile range of 25 pg/mL in the non-infected group. The basic fibroblast growth factor result came from a different comparison. Participants with mild functional limitations within the long COVID group had a median concentration of 24 pg/mL, with an interquartile range of 7 pg/mL, 25% lower than the 32 pg/mL median recorded among spontaneous resolvers.

The spontaneous-resolver group had an interquartile range of 24 pg/mL, and the reported p value was 0.025. This lower concentration was associated specifically with the mild long COVID subgroup, not with the overall long COVID group. Investigators also examined whether the measured cytokines varied together.

Pairwise correlation analysis showed strong positive associations among cytokines in three long COVID subgroups when compared with the non-infected group. In contrast, principal component analysis did not detect a coordinated pattern of cytokine variation that was specific to any group. The two approaches therefore produced different views of the data: correlations identified relationships between individual measurements, whereas the multivariate analysis did not resolve a group-specific pattern across the measured cytokines.

Overall, the findings suggest that altered immune and inflammatory signaling may be present in some people with long COVID and may differ according to functional status. The researchers specifically interpreted elevated interleukin-12 and reduced basic fibroblast growth factor as possible signs of persistent immune activation and subgroup-specific biology. However, the statistical results were marginal, the analysis was exploratory and the cross-sectional design could not determine whether the measured differences preceded illness, developed during acute infection or persisted through long COVID.

The study also comes with clear scope limitations. It assessed blood concentrations at a single point in a cohort of 127 participants, and most long COVID participants had mild or moderate functional limitations, with only 10 classified as severely limited. The results identify candidate signals for further investigation, but they do not establish a clinically validated blood test for long COVID.

Subject of Research: Exploratory cross-sectional profiling of blood cytokines and growth factors in long COVID

Article Title: Blood biomarkers of long COVID: A cross-sectional evaluation of key cytokines and the coordination of inflammation

Article References: Thomas, C., Ashton, R. E., Pretorius, E., Owen, R., Nunes, M., Pretorius, J. H., Shawa, I. T., Chidley, C., & Faghy, M. A. (2026). Blood biomarkers of long COVID: A cross-sectional evaluation of key cytokines and the coordination of inflammation. PLOS One, 21(10), e0360525. https://doi.org/10.1371/journal.pone.0360525

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0360525

Keywords: long COVID, blood biomarkers, interleukin-12, fibroblast growth factor, cytokines, immune activation, SARS-CoV-2, cross-sectional study, functional status, Blood, biomarkers, long