Blood biomarkers-defined subgroups show heterogeneity in post-acute COVID-19 syndrome: a rationale for precision medicine.

Acute COVID-19 can cause a post-infectious syndrome in a significant percentage of patients, with multifacted and long lasting symptoms. We hypothesized that this Post-Acute COVID syndrome (PASC) could result from various underlying causes, which may compromise the demonstration of efficacy for treatments evaluated on cohorts of heterogeneous patients. To assess the feasibility of stratifying or characterizing subgroups of post-COVID-19 patients consistent with different indications in a precision medicine perspective, we tested serum biomarkers in a pilot cross-sectional study of patients with neuro-cognitive symptoms from the Northwestern University post-COVID-19 clinic (Chicago,USA). Patient health status was evaluated with the use of standardized PROMIS questionnaires and underwent validated cognitive tests with the NIH Toolbox. Serum biomarkers were chosen as proteins known to be involved in the pathogenic features of a neuro-inflammatory disease, i.e., multiple sclerosis, with a final selection of the most discriminant ones. A multi-isotypes serology against SARS-CoV-2 spike and nucleocapsid antigens was performed to allow detailed analyses of the humoral immune status. Despite the limited numbers of this feasibility study, results showed that clinical data could not differentiate PASC patients with persisting neuro-cognitive impairment, while three major PASC subgroups were identified with serum biomarkers according to the presence or absence of the HERV-W ENV soluble protein combined with neurofilaments light chains and, to a lesser extent, with elevated levels of IL-6. SARS-CoV-2 serological results in PASC compared to healthy controls also revealed a significant increase of anti-Spike and/or Nucleocapsid IgM, IgA and, unexpectedly, IgE. For IgG, a significant difference was observed with Nucleocapsid only since anti-Spike IgG titers were normally elevated in vaccinated controls. This multi-Ig isotypes serology may provide additional information on the infectious and immunological status of individual patients and should be considered in face of a potential viral persistence in some individuals. Altogether the results show the feasibility of using serum biomarkers to discriminate relevant subgroups or individual patients for precision medicine indications in post-COVID syndromes. This pilot study paves the way to further exploring biological assays for the definition of subtypes of PASC, also called long COVID, useful for the choice of relevant therapeutic strategies.