Long COVID shows IL-1 pathway dysregulation without a discrete circulating biomarker signature
Related Experiment Videos
Francisco Muñoz-López1, Marissa Flores-Santamaría1, Rebeca Santano2,3,4
1IrsiCaixa, Badalona, Barcelona, Spain.
Introduction:
Long COVID (LC) is characterized by persistent and, often, disabling symptoms, yet its biological basis remains unclear. Multiple mechanisms, including immune dysregulation, endothelial dysfunction, and persistence of SARS-CoV-2 components, have been proposed, although it is unknown whether these define distinct biological subtypes or overlapping processes.
Methods:
We conducted a cross-sectional analysis of 312 individuals, including 139 people with LC (PWLC), 99 COVID-19-recovered controls (both groups sampled a median of 8 months after primary SARS-CoV-2 infection), and 74 uninfected controls, from an unvaccinated population, thereby minimizing major sources of biological and epidemiological variability. Circulating immune and endothelial biomarkers and plasma SARS-CoV-2 RNA were assessed, together with serological signatures associated with herpesvirus reactivation and SARS-CoV-2-specific humoral responses. Associations with symptom persistence were analyzed using multivariable models and machine learning approaches.
Results:
Most soluble biomarker differences primarily distinguished previously infected individuals from uninfected controls rather than PWLC from recovered participants. Increased IL-1 receptor antagonist (IL-1RA) levels, together with reduced IL-1β/IL-1RA ratios, were the immune alterations most strongly associated with LC, while P-selectin was the endothelial marker showing a suggestive association with symptom persistence. Plasma SARS-CoV-2 RNA was detected at low and comparable frequencies in PWLC and recovered individuals, while Ct values tended to be lower among RNA-positive PWLC not reaching statistical difference. Epstein-Barr virus serological profiles were characterized by lower latency- and higher reactivation-associated responses in PWLC, whereas SARS-CoV-2-specific antibody levels were comparable between groups. Integrated biomarker profiles discriminated prior infection more effectively than LC status, and expansion to multimodal predictors did not clearly improve discrimination between PWLC and recovered participants.
Discussion:
Overall, LC was associated with overlapping immune, endothelial, and virological alterations rather than discrete biomarker-defined subtypes.
