Molecular Determination of Risk for PASC by High Sensitivity Serological Analyses of Inflammatory Pathway Markers, Prior Viral Histories and Autoantibodies

Introduction: The pathological mechanisms underlying Long COVID remain poorly understood, though it is likely that Long COVID results from the combination of an individual's pre-existing baseline conditions and their response to SARS-CoV-2 infection. Studies that quantify immune biomarkers are necessary to better understand an individual's risk for developing Long COVID.

Objective: In this study, we measured antibodies targeting viral antigens and autoantigens, SARS-CoV-2 viral antigens, and cytokines in blood samples collected post-SARS-CoV-2 infection to identify protein biomarkers linked with Long COVID.

Methods: Serum samples collected 0, 3, and 6 months after SARS-CoV-2 infection were obtained from 115 individuals in the RECOVER (Researching COVID to Enhance Recovery) cohort. Individuals within the RECOVER cohort were determined to have Long COVID using a symptom-based index. Here, individuals that were classified as having Long COVID at 6, 9, and 12 month follow-up timepoints were considered Long COVID-positive, whereas those who had no Long COVID symptoms at 6, 9, and 12 months were used as controls. Phage immuno-precipitation sequencing (PhIP-Seq) was used to profile viral and autoimmune antibodies, and single molecule array (Simoa) assays were used to quantify SARS-CoV-2 antigens, anti-SARS-CoV-2 antibodies, and cytokines in the collected serum samples.

Results: At 3 and 6 months post-infection, levels of autoantibodies targeting four proteins, including advillin (p92), SKI family transcriptional corepressor 1 (SKOR1), centrosomal protein 85L (CEP85L), and titin, were found to be statistically different between individuals with Long COVID and controls. The concentration of CRP and IL-6 was significantly elevated in the Long COVID group at 3 months, and the concentration of IL-8 was significantly decreased at 6 months for the Long COVID group. In addition, IL-17, CRP, and autoantibodies against p92 and CEP85L were positively correlated with Long COVID symptoms, such as brain fog, dizziness, shortness of breath, fatigue, post-exertional malaise, heart palpitations, and cough, while IL-10 was negatively correlated with many Long COVID symptoms.

Conclusion/Discussion: Our study suggests that the quantification of specific protein biomarkers, including autoantibodies and cytokines, within 6 months post-infection can predict the development of Long COVID.

Key Topics:

• Assay and in vitro studies to gain mechanistic insights
• Biomarker, in-depth phenotyping assays and in vitro studies using tissue and other biospecimens
• Chronic immune dysfunction
• Collaborative and systems biology approaches
• Long COVID and other chronic conditions
• Long-term follow-up of the RECOVER Cohorts
• Viral persistence/reactivation