Long COVID: Deep single-cell immunophenotyping and machine learning reveal a general signature for fatigue.

Abstract The post COVID-19 condition, commonly referred to as “Long COVID” (LC), is a constellation of long-lasting and debilitating symptoms following acute SARS-CoV-2 infection, which closely resembles other post-infective fatigue states. The underlying immunological disturbances of LC are poorly understood. The present study included 12 to 25-year-olds with and without mild SARS-CoV-2 infection, who were prospectively followed for six months after infection and assessed according to the WHO definition of post COVID-19 condition, resulting in four groups (“Long COVID” (LC), recovered convalescents (RC), fatigued controls (FC), healthy controls (HC)). Mass cytometry was used to profile peripheral blood mononuclear cells. We found higher frequencies of Terminal NK cells and Double Negative B cells, and higher CD4 + T cell activation and exhaustion in the two groups characterized by persistent fatigue (LC, FC), while no specific immune abnormality pertaining only to LC. This points to a shared underlying pathophysiology in LC and other forms of fatigue.