Almost a year and a half after infection, researchers investigated whether long-term COVID-19 infections leave measurable traces of inflammation and nerve damage in the blood, and the results cast doubt on assumptions about sustained immune activation.
Study: Long-lasting coronavirus: assessment of circulating markers suggests absence of brain neuron damage, neuroinflammation, and systemic inflammation – controlled study. Image credit: p.ill.i / Shutterstock
Recent research published in journals scientific report We analyzed circulating biomarkers of systemic inflammation and neuroinflammation in patients with long-term novel coronavirus (LC).
Background and long-term spread of the new coronavirus infection
LC is emerging as a global health problem, and its prevalence increases with repeated exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The estimated prevalence of LC increased from 60 million to 400 million people worldwide between 2020 and 2024. Some studies with up to 2 years of observation have found that lingering symptoms remain essentially unchanged over time, while other studies suggest that symptoms become milder.
Acute coronavirus disease 2019 (COVID-19) is considered to be a multisystem disease, but the mechanisms underlying the chronic phase are unclear. Some hypotheses suggest that LC may resemble other post-infectious syndromes with prolonged symptoms without ongoing organ damage, while others emphasize a reactivated viral reservoir and persistent organ damage. Additionally, studies have provided evidence of target organ involvement, such as neuronal damage.
However, many studies have been conducted early in LC, within months of infection, which may reflect ongoing organ damage or persistence of the virus during healing. Additionally, although early studies described a variety of symptoms, this changed over time, with cognitive impairment and fatigue emerging as the main features of LC. These observations are consistent with those in diseases following viral infection, where symptoms often become chronic, but inflammatory biomarkers usually normalize.
Study design and participant selection
In this study, researchers analyzed circulating biomarkers of neuroinflammation and systemic inflammation in LC patients. This case-control study was conducted in a Norwegian hospital from January 1, 2022 to April 1, 2024. Eligible participants were between 16 and 80 years old and had a confirmed SARS-CoV-2 infection. LC cases met the National Institute for Healthcare Excellence (NICE) criteria for LC: persistent symptoms for more than 12 weeks that cannot be explained by alternative diagnoses.
Controls were individuals who had fully recovered from SARS-CoV-2 infection and had no persistent symptoms. Those with chronic inflammatory diseases, autoimmune diseases, anemia, hypothyroidism, cancer, untreated comorbidities affecting fatigue, and those using systemic corticosteroids were excluded. Regular biochemical and blood tests, including CRP, were performed at the hospital.
How to measure biomarkers
Pro-inflammatory cytokines, namely interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α), were measured using the MSD S-Plex electrochemiluminescence immunoassay platform. In addition, glial fibrillary acidic protein (GFAP, a neuroinflammation biomarker), neurofilament light (NfL, a neuroinjury biomarker), trigger receptor expressed on myeloid cells 2 (TREM2), CRP, IL-6, IL-1β, and TNF-α were measured using an ultrasensitive nucleic acid-linked immunosandwich assay (NULISA).
Research results on inflammatory and neurological biomarkers
This study recruited 112 individuals, of whom 96 were included in the final analytic sample. Their average age was 46.7 years. Most participants were female (85.4%) and the median time since diagnosis of COVID-19 was 69 weeks. LC cases and recovered controls were well matched for gender, age, and time since COVID-19 infection.
CRP measured by routine hospital analysis was not significantly different between cases and controls. TNF-α and IL-6 levels were slightly elevated in LC cases compared to recovered controls. NULISA revealed that LC cases had nominally (in unadjusted analysis) increased levels of inflammatory markers (CRP, TREM2, TNF-α, and IL-6) than controls. In contrast, GFAP and NfL were not significantly different between groups.
After false discovery rate (FDR) correction, inflammatory biomarkers were no longer significantly different between LC cases and controls, suggesting that differences either do not exist or are too subtle to be reliably detected in this cohort. Finally, Spearman correlation analysis revealed no correlation between inflammatory biomarkers and symptom severity, suggesting that the levels of these biomarkers do not predict symptom burden in our cohort.
Conclusions and limitations of the study
Taken together, this study found no significant differences in neurological and inflammatory biomarkers between LC cases and recovered controls at 69 weeks post-SARS-CoV-2 infection. These results do not support evidence of overt immune activation, inflammation, or neurological damage in the studied cohort at this late stage of infection. This discrepancy with previous studies may reflect differences in follow-up period, as the longer follow-up in this study may have allowed sufficient time for resolution of acute inflammation and viral clearance.
One reason previous studies have found ongoing immune activation and inflammation in LC is that their cohorts have included people with pre-existing chronic inflammatory or autoimmune conditions who exhibit many of the same inflammatory markers and clinical symptoms as LC. The current cohort was designed to minimize potential confounding by such conditions and thus better separate LC-related biological signals.
Limitations of this study include the small sample size, cross-sectional design that precludes causal inferences, the use of a selected panel of biomarkers that may imply that other inflammatory pathways are active, the reliance on blood-based biomarkers without paired cerebrospinal fluid or neuroimaging data, and the use of assay outputs reported in normalized protein expression units rather than absolute concentrations, which may limit comparisons with external reference values.
Overall, the findings do not support persistent systemic inflammation, neuroinflammation, or neurological damage detectable in the blood at this stage of prolonged COVID-19 infection, but the authors note that extremely low levels of immune activation, which may be below current biomarker detection thresholds, or other mechanisms may still contribute to the symptoms and warrant further investigation in larger cohorts.
Reference magazines:
- Omdal R, Renning OB, Johnson G, et al. (2026). Long-term coronavirus: controlled study in which assessment of circulating markers suggests absence of cranial nerve damage, neuroinflammation, and systemic inflammation. scientific report. DOI: 10.1038/s41598-026-40142-0, https://www.nature.com/articles/s41598-026-40142-0
