Post-COVID symptoms are associated with endotypes reflecting poor inflammatory and hemostatic modulation

Area of Science:

• Immunology
• Genomics
• Systems Biology

Background:

• Persistent symptoms after COVID-19 infection, known as long COVID, affect nearly half of survivors.
• The underlying pathophysiology of long COVID remains poorly understood, suggesting involvement of multiple host systems.

Purpose of the Study:

• To investigate the mechanisms of long COVID using a systems-biology approach.
• To identify distinct patient endotypes and their associated gene expression signatures for potential clinical stratification.

Main Methods:

• RNA sequencing (RNA-seq) of whole blood from COVID-19 patients during hospitalization and post-discharge.
• Differential gene expression analysis, pathway enrichment, and machine learning to identify mechanisms of post-COVID symptoms.
• Validation of identified endotypes in an external patient cohort.

Main Results:

• Patients with and without post-COVID symptoms exhibited different temporal gene expression changes, particularly in inflammatory and coagulation pathways.
• Three patient endotypes were identified: 'Resolved', 'Suppressive', and 'Unresolved', with distinct inflammatory/hemostatic response patterns.
• The 'Unresolved' and 'Suppressive' endotypes were associated with higher rates of long COVID symptoms and were validated externally using gene expression signatures.

Conclusions:

• Patient heterogeneity is a key factor in long COVID pathophysiology.
• Two endotypes, 'Unresolved' and 'Suppressive', are linked to persistent inflammation or coagulation abnormalities and increased long COVID symptoms.
• Blood gene biomarkers can potentially stratify patients into endotypes, enabling personalized treatment strategies for long COVID.