Author: John Murphy, President, COVID-19 Long-haul Foundation
Abstract
Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), presents with a complex array of symptoms affecting multiple organ systems. Accurate diagnosis and monitoring remain challenging due to the absence of standardized biomarkers and imaging protocols. This article synthesizes emerging evidence on diagnostic biomarkers—including D-dimer, IL-6, CRP, ferritin, fibrinogen, endothelial microparticles, and platelet markers—and advanced imaging modalities such as SPECT, MRI perfusion, and PET scans. We also examine novel blood-based assays for spike protein and clot burden. These tools offer promise for stratifying disease severity, guiding treatment, and validating therapeutic response.
1. Introduction
Long COVID affects an estimated 10–30% of individuals following SARS-CoV-2 infection. Symptoms range from fatigue and brain fog to cardiovascular, pulmonary, and immunological dysfunction. Despite its prevalence, Long COVID lacks a definitive diagnostic test. Clinicians rely on symptom clusters and exclusionary criteria, which complicates early intervention and research standardization.
Recent advances in biomarker discovery and imaging technologies offer a path toward objective diagnosis. This article reviews the most promising diagnostic tools and their clinical relevance.
2. Inflammatory and Coagulation Biomarkers
D-dimer
Elevated D-dimer levels are associated with persistent clotting activity and microvascular injury. In Long COVID, D-dimer remains elevated months after infection, correlating with fatigue and dyspnea.
IL-6
Interleukin-6 is a key cytokine in the inflammatory cascade. Persistent IL-6 elevation is linked to neuroinflammation, endothelial dysfunction, and cognitive impairment.
CRP and Ferritin
C-reactive protein and ferritin are acute-phase reactants. Elevated levels indicate ongoing inflammation and oxidative stress. These markers are useful for tracking disease activity and response to anti-inflammatory therapies.
Fibrinogen
Fibrinogen contributes to clot formation and is often elevated in Long COVID. Misfolded fibrinogen may form amyloid-like clots resistant to fibrinolysis.
3. Endothelial and Platelet Biomarkers
Endothelial Microparticles (EMPs)
EMPs are released during endothelial injury and reflect vascular stress. Elevated EMPs are associated with microclot burden and hypoperfusion.
Platelet Activation Markers
Markers such as P-selectin and CD62P indicate platelet hyperactivation. These markers correlate with thromboinflammation and may guide anticoagulant therapy.
4. Imaging Modalities
SPECT/CT
Ventilation/perfusion SPECT/CT reveals perfusion defects in Long COVID patients with respiratory symptoms. Bonnefoy et al. (2025) found significant V/Q mismatches in post-COVID cohorts.
MRI Perfusion
Functional MRI detects cerebral hypoperfusion, especially in the default mode and frontoparietal networks. These findings correlate with cognitive symptoms such as brain fog and executive dysfunction.
PET Scans
PET imaging using [18F]-FDG and [11C]K-2 tracers reveals inflammation and synaptic remodeling. Studies from Mount Sinai and Applied Radiology show persistent cardiac and pulmonary abnormalities up to one year post-infection.
5. Emerging Blood-Based Assays
Spike Protein Detection
Novel assays detect circulating spike protein months after infection or vaccination. These assays offer a direct measure of spike persistence and correlate with symptom severity.
MicroRNA Panels
MicroRNAs regulate immune and inflammatory pathways. Paval et al. (2025) identified miRNA signatures in Long COVID patients that may serve as diagnostic biomarkers.
Extracellular Vesicle (EV) Biomarkers
EVs carry molecular cargo from injured cells. Researchers at TGen and Lundquist Institute identified EV-based biomarkers that differentiate Long COVID from other post-viral syndromes.
6. Integration and Clinical Utility
Combining biomarkers with imaging enhances diagnostic precision. For example, elevated IL-6 and D-dimer paired with PET-detected inflammation may stratify patients for anti-inflammatory or anticoagulant therapy. Longitudinal tracking of biomarkers can validate treatment response and guide clinical decision-making.
7. Conclusion
Diagnostic biomarkers and imaging modalities are transforming Long COVID care. From inflammatory markers to advanced neuroimaging, these tools offer objective measures of disease activity. Continued research and standardization are essential for integrating these diagnostics into clinical practice and improving patient outcomes.
📎 References
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- MicroRNAs in long COVID: roles, diagnostic biomarker potential and detection
- Researchers find important biomarkers in long COVID
- The First Reliable Biomarker for Long COVID?
- EV biomarker could be breakthrough for Long COVID diagnosis
- Researchers identify a potential biomarker for long COVID