Persistent neutrophil maturation deficits associate with cognitive impairment in individuals with post-acute sequelae of COVID-19

Introduction Post-COVID-19 condition, or post-acute sequelae of COVID-19 (PASC), is characterized by persistent cognitive impairments and immune dysregulation. While neutrophils are critical in acute COVID-19, whether their long-term functional dysregulation contributes to PASC, remains unclear. Thus, we investigated the links between immune system changes, symptom severity and cognitive impairment in PASC. Methods In this cross-sectional study, we enrolled 40 individuals with self-reported issues with COVID-19 recovery (PASC) and 37 fully recovered (REC) volunteers. Participants were post-infection at either TP1 (from 6 up to 18 months post-infection, 7 PASC, 20 REC) or at TP2 (from 19 up to 36 months post-infection, 33 PASC, 17 REC). We evaluated the Newcastle post-COVID-19 Syndrome Follow Up Screening (NC) scores for symptom severity, and neuropsychological tests for memory, attention, and executive function. Peripheral blood was analyzed using multicolor flow cytometry, ELISA, clustering, and multivariate regression. Results PASC participants in both the TP1 cohort and the TP2 cohort, demonstrated increased NC scores and significant changes in neutrophil numbers and subset composition. In the TP1 cohort, the PASC group showed an increased frequency of activated CD16 + CD62L low neutrophils and a reduced frequency of CXCR4 + TREM-1 + CCR2 + polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). This was accompanied by elevated soluble TNF receptor 1 (sTNFR1) and decreased sTNFR2 and CXCL12. In the TP2 cohort, PMN-MDSC levels were comparable between REC and PASC groups, alongside increased emergency granulopoiesis regulators IL-3 and IL-6. Multivariate regression revealed significant associations between PMN-MDSC signatures, granulopoiesis-related markers, NC scores, and cognitive test scores in either the TP1 or the TP2 cohort. These results represent cross-sectional observations in participants assessed within the respective post-infection intervals, rather than longitudinal evidence of persistence. The results show that dysregulated granulopoiesis and neutrophil maturation are present even at 18 and 36 months in PASC individuals, potentially associating with overall symptom severity and cognitive impairment. Conclusions Despite limitations in cohort size, requiring validation of the associations in larger cohorts, our findings may contribute to the further understanding of PASC and future new transitional perspectives for PASC management.