[Abstract] Long-COVID at 5 years: persistent neuroinflammation and progressive axonal damage in hospitalized patients, 2026, Pasculli et al

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P239 Long-COVID at 5 years: persistent neuroinflammation and progressive axonal damage in hospitalized patients

Pasculli, P; Zingaropoli, MA; Antonacci, M; Dominelli, F; Ciccone, F; Lichtner, M; Ciardi, MR; Mastroianni, CM

Background
Long-COVID sequelae remain poorly characterized, particularly regarding long-term neurological impact beyond one year. This study aimed to describe persistent symptoms in hospitalized patients, evaluate vaccination impact, and assess CNS damage via plasma biomarkers (NfL, GFAP) over a 5-year follow-up.

Materials and Methods
A longitudinal cohort study was conducted on hospitalized COVID-19 patients. Clinical assessments included symptoms, chest CT, and lung function. Plasma samples were collected for a subgroup of study population at admission (T0), 3-months (T1), and 5-years (T2) post-discharge, and compared to age/sex-matched healthy donors (HD).

Results
Overall, 144 COVID-19 patients with a median age (IQR of 58 [49–66] years) were included. During hospitalization, 51.4% (74/144) developed ARDS and 18.8% (27/144) of COVID-19 patients died. Fatigue (57%) at T1 and dyspnea (14.2%) at T2 were the most reported symptoms. Compared with women, men showed a lower risk of presenting at least one long COVID symptom (OR 0.42; 95% CI, 0.23-0.73, P = .003). At T1, chest CT scans showed abnormalities in two-thirds of patients, lung function abnormalities in half of the patients. Hospitalized patients are at a higher risk of lung injury. (OR 2.17; 95% CI, 1.11-4.23, P = .023). Age increased risk of lung impairment (OR 1.03; 95% CI, 1.01-1.04, P = .001). Vaccination was associated with reduced hospitalization, respiratory support, cardiopulmonary function abnormalities, and lung parenchymal damage, but not long COVID symptom occurrence.

In the biomarkers subgroup (n=77), NfL and GFAP were elevated versus HDs at all timepoints (T0: p<0.0001 and p<0.0001, respectively; T1: p<0.0001 and p=0.0220, respectively; T2: p<0.0001 and p<0.0001, respectively).

Longitudinally, NfL increased significantly at T2 versus T0 (p=0.0053) with no change at T1. Conversely, GFAP decreased at T1 (p=0.0016) but showed no difference at T2 versus T0.

Conclusion
Findings confirm acute CNS involvement. Notably, longitudinal evaluation reveals a dissociation between astrocytic reactivity and axonal damage.

While GFAP suggests resolution of acute inflammation followed by chronic low-grade gliosis, the significant NfL increase at 5 years indicates potential progressive axonal injury. This aligns with evidence suggesting SARS-CoV-2 may accelerate neurodegenerative processes.

Persistent marker elevation underscores the need for long-term neurological monitoring.

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