A Short Corticosteroid Course Reduces Symptoms and Immunological Alterations Underlying Long-COVID

Abstract

Despite the growing number of patients with persistent symptoms after acute SARS-CoV-2 infection, the pathophysiology underlying long-COVID is not yet well characterized, and there is no established therapy. We performed a deep immune profiling in nine patients with persistent symptoms (PSP), before and after a 4-day prednisone course, and five post-COVID-19 patients without persistent symptoms (NSP). PSP showed a perturbed distribution of circulating mononuclear cell populations. Symptoms in PSP were accompanied by a pro-inflammatory phenotype characterized by increased conventional dendritic cells and augmented expression of antigen presentation, co-stimulation, migration, and activation markers in monocytes. The adaptive immunity compartment in PSP showed a Th1-predominance, decreased naïve and regulatory T cells, and augmentation of the PD-1 exhaustion marker. These immune alterations reverted after the corticosteroid treatment and were maintained during the 4-month follow-up, and their normalization correlated with clinical amelioration. The current work highlights an immunopathogenic basis together with a possible role for steroids in the treatment for long-COVID.

Keywords: corticosteroids; immunological alterations; long-COVID.

Figure 1

Deep immune profiling detected alterations in post-COVID-19 patients with persistent symptoms, which were corrected with a short course of corticosteroids. (a) Study design included three groups of post-COVID-19 patients: five subjects who recovered completely (green, NSP) and nine subjects with persistent symptoms (orange, PSP), eight of whom were sampled again after 4 days of prednisone treatment (blue, TTP). (b) Principal component analysis (PCA) based on all flow cytometry data. (c) Contribution of each variable to Dimensions 1 and 2 of PCA. (d) Unsupervised hierarchical clustering analysis and heatmap of log10-transformed and center-scaled variables.

Figure 2

Immunological alterations in PSP include dysregulated innate and adaptive populations together with higher expression of activation factors. Comparison between NSP, PSP, TTP, and TTP+4M of (a) conventional dendritic cells (CD11b+ DC), natural killer T lymphocytes (NKT), plasmacytoid DC (CD123+ pDC), and innate lymphoid cells (ILC); (b) naïve, memory, and follicular helper T CD4+ lymphocytes; (c) expression of HLA-DR and CD38 and expression of CD95 and PD-1 on CD4+ T lymphocytes; (d) subsets of memory CD4+ T cells based on CXCR3 and CCR6 expression; (e) subsets of follicular helper T CD4+ lymphocytes; (f) regulatory T cells (Treg); (g) naïve, central memory (TCM), effector memory (TEM), and effector memory re-expressing CD45RA (TEMRA) CD8+ T cells; and (h) naïve, non-class-switched memory (NCS), class-switched memory (CS), and plasmablast B cells. Grey regions depict percent populations ranges, if available, obtained from groups of representative healthy donors in our clinical immunology laboratory. In (b), tSNEs were performed by using all 37 fluorochromes (see Methods); and in (c), tSNEs were performed in total CD4+ cells and using CXCR5, CD27, CCR7, CD45RA, CCR6, and CXCR3. *, p < 0.05; **, p < 0.01; ***, p < 0.001.