Identification of an immunological signature of long COVID syndrome, 2025, Guerrera et al.

[SNT Gatchaman]

Identification of an immunological signature of long COVID syndrome
Guerrera, Gisella; Sambucci, Manolo; Timperi, Eleonora; Picozza, Mario; Misiti, Andrea; Placido, Roberta; Corbisiero, Silvia; D’Orso, Silvia; Termine, Andrea; Fabrizio, Carlo; Gargano, Francesca; Eleuteri, Sharon; Marchioni, Luisa; Bordoni, Veronica; Coppola, Luigi; Iannetta, Marco; Agrati, Chiara; Borsellino, Giovanna; Battistini, Luca

INTRODUCTION
Acute COVID-19 infection causes significant alterations in the innate and adaptive immune systems. While most individuals recover naturally, some develop long COVID (LC) syndrome, marked by persistent or new symptoms weeks to months after SARS-CoV-2 infection. Despite its prevalence, there are no clinical tests to distinguish LC patients from those fully recovered. Understanding the immunological basis of LC is essential for improving diagnostic and treatment approaches.

METHODS
We performed deep immunophenotyping and functional assays to examine the immunological profiles of LC patients, individuals with active COVID-19, recovered patients, and healthy donors. This analysis assessed both innate and adaptive immune features, identifying potential biomarkers for LC syndrome. A Binomial Generalized Linear Model (BGLM) was used to pinpoint immune features characterizing LC.

RESULTS
COVID-19 patients exhibited depletion of innate immune cell subsets, including plasmacytoid and conventional dendritic cells, classical, non-classical, and intermediate monocytes, and monocyte-derived inflammatory dendritic cells. Elevated basal inflammation was observed in COVID-19 patients compared to LC patients, whose immune profiles were closer to those of healthy donors and recovered individuals. However, LC patients displayed persistent immune alterations, including reduced T cell subsets (CD4, CD8, Tregs) and switched memory B cells, similar to COVID-19 patients. Through BGLM, a unique adaptive immune signature for LC was identified, featuring memory CD8 and gd T cells with low proliferative capacity and diminished expression of activation and homing receptors.

DISCUSSION
The findings highlight a unique immunological signature associated with LC syndrome, characterized by persistent adaptive immune dysregulation. While LC patients displayed recovery in innate immune profiles comparable to healthy and Recovered individuals, deficits in T cell and memory B cell populations were evident, differentiating LC from full recovery. These findings provide insights into LC pathogenesis and may support the development of diagnostic tools and targeted therapies.

Link | PDF (Frontiers in Immunology) [Open Access]

 

[Yann04]

Does anyone else desperately wish these studies were on specific subtypes ie. POTS, Post-ICU syndrome, ME etc.

I feel like we have so much useful data diluted down with arbitrary definitions of limited usefulness.

 

[Eleanor]

There were only 10 Long Covid patients in this study.

 

[SNT Gatchaman]

The immunological features with the highest GLM accuracy (>0.94) were predominantly represented by adaptive immune elements. Notably, the Ki67-proliferating memory CD8 (mCD8) T cells emerged as the first variable, with lower counts of Ki67+ - mCD8 T cells observed in LC compared to HD/Recovered individuals.

Subsequently, both mCD8- and gamma delta (gd) & double negative (DN)-CXCR5 and CCR6 expressing cells were found lower in LC than in HD/Recovered individuals. The same trend of Ki67 expression in mCD8 T cells was observed in gamma delta (gd) & double negative (DN) cells.

Of particular interest, only the number of NcMono2 producing TNF-a was identified as a predictor within the variables derived from the myeloid compartment. These data suggested that LC patients display lower T cell proliferation and reduced expression of T cell activation markers compared to HD and Recovered subjects […] and may serve as specific signature to distinguish LC condition.

Despite the model being built on a relatively small cohort of LC patients (N=10), it exhibited the ability to classify LC patients from HD and Recovered subjects, primarily based on adaptive immunological parameters.