Serum IL-23, IL-10, and TNF-α predict in-hospital mortality in COVID-19 patients.

Objective: The hyperinflammatory response, caused by severe acute respiratory syndrome-2 (SARS-CoV-2), is the most common cause of death in patients with coronavirus disease 2019 (COVID-19). The etiopathogenesis of this illness is not fully understood. Macrophages appear to play a key part in COVID-19's pathogenic effects. Therefore, this study aims to examine serum inflammatory cytokines associated with the activation state of macrophages in COVID-19 patients and attempt to find accurate predictive markers for disease severity and mortality risk in hospital. Methods: 180 patients with COVID-19 and 90 healthy controls (HCs) participated in this study. Patients were divided into three different subgroups, mild (n=81), severe (n=60), and critical groups (n=39). Serum samples were collected and IL (Interleukin)-10, IL-23, tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), IL-17, monocyte chemoattractant protein-1 (MCP-1) and chemokine ligand 3 (CCL3) were determined by ELISA. In parallel, myeloperoxidase (MPO) and C-reactive protein (CRP) were measured using colorimetric and electrochemiluminescence methods, respectively. Data were collected, and their associations with disease progression and mortality were assessed using regression models and receiver operating characteristic (ROC) curves. Results: Compared to HCs, a significant increase in IL-23, IL-10, TNF-α, IFN-γ and MCP-1, were observed in COVID-19 patients. Serum levels of IL-23, IL-10, and TNF-α were significantly higher in COVID-19 patients with critical cases compared to mild and severe cases, and correlated positively with CRP level. However, non-significant changes were found in serum MPO and CCL3 among the studied groups. Moreover, significant positive association has been observed among increased IL-10, IL-23 and TNF-α in serum of COVID-19 patients. Furthermore, a binary logistic regression model was applied to predict death's independent factors. Results showed that IL-10 alone or in combination with IL23 and TNF-α are strongly linked with non-survivors in COVID-19 patients. Finally, ROC curve results uncovered that IL-10, IL-23 and TNF-α were excellent predictors for prognosing COVID-19. Conclusion: The elevations of IL-10, IL-23, and TNF-α levels were seen in severe and critical cases of COVID-19 patients and their elevations were linked to the in-hospital mortality of the disease. A prediction model shows that the determination of these cytokines upon admission is important and should be done on COVID-19 patients as a way of evaluating the prognosis of the disease. COVID-19 Patients with high IL-10, IL-23, and TNF-α on admission are more likely to experience a severe form of the disease; therefore, those patients should be cautionary monitored and treated.

Kv1.3 blockade by ShK186 modulates CD4+ effector memory T-cell activity of patients with Granulomatosis with polyangiitis.

OBJECTIVES: Granulomatosis with polyangiitis (GPA) is a chronic relapsing systemic autoimmune vasculitis. Current treatment of GPA is unsatisfactory as it relies on strong immunosuppressive regimens, with either cyclophosphamide or rituximab, that reduce the immunogenicity of several vaccines and are risk factors of severe form of COVID-19. This emphasizes the need to identify new drug target and to develop treatment strategies with less harmful side effects. Since CD4+ effector memory T cells (TEM) play a key role in the pathogenesis of GPA, we aimed in this study to modulate CD4+TEM cell activity via Kv1.3 blockade using the specific peptide inhibiter, ShK-186. METHODS: Peripheral blood of 27 GPA-patients in remission and 16 age- and sex-matched healthy controls (HCs) were pre-incubated in vitro in the presence or absence of ShK-186, followed by stimulation with PMA, calcium ionophore and brefeldin-A. The effect of ShK-186 on the cytokine production (IFNγ, TNFα, IL-4, IL-17, IL-21) within total and subsets of CD4+TH cells were assessed using flow cytometry. RESULTS: ShK-186 reduced the expression level of IFNγ, TNFα, IL-4, IL-17, and IL-21 in CD4+TH cells from GPA-patients in vitro. Further analysis performed on sorted CD4+T cell subsets, revealed that ShK-186 predominantly inhibited the cytokine production of CD4+TEM cells. ShK-186 treatment reduced the production of the pro-inflammatory cytokines to the level seen in CD4+ TH cells from HCs. CONCLUSIONS: Modulation of cellular effector function by ShK-186 may constitute a novel treatment strategy for GPA with high specificity and less harmful side effects.

Ferric carboxymaltose and SARS-CoV-2 vaccination-induced immunogenicity in kidney transplant recipients with iron deficiency: The COVAC-EFFECT randomized controlled trial.

Background: Kidney transplant recipients (KTRs) have an impaired immune response after vaccination against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Iron deficiency (ID) may adversely affect immunity and vaccine efficacy. We aimed to investigate whether ferric carboxymaltose (FCM) treatment improves humoral and cellular responses after SARS-CoV-2 vaccination in iron-deficient KTRs. Methods: We randomly assigned 48 iron-deficient KTRs to intravenous FCM (1-4 doses of 500mg with six-week intervals) or placebo. Co-primary endpoints were SARS-CoV-2-specific anti-Receptor Binding Domain (RBD) Immunoglobulin G (IgG) titers and T-lymphocyte reactivity against SARS-CoV-2 at four weeks after the second vaccination with mRNA-1273 or mRNA-BNT162b2. Results: At four weeks after the second vaccination, patients receiving FCM had higher plasma ferritin and transferrin saturation (P<0.001 vs. placebo) and iron (P=0.02). However, SARS-CoV-2-specific anti-RBD IgG titers (FCM: 66.51 [12.02-517.59] BAU/mL; placebo: 115.97 [68.86-974.67] BAU/mL, P=0.07) and SARS-CoV-2-specific T-lymphocyte activation (FCM: 93.3 [0.85-342.5] IFN-É£ spots per 106 peripheral blood mononuclear cells (PBMCs), placebo: 138.3 [0.0-391.7] IFN-É£ spots per 106 PBMCs, P=0.83) were not significantly different among both arms. After the third vaccination, SARS-CoV-2-specific anti-RBD IgG titers remained similar between treatment groups (P=0.99). Conclusions: Intravenous iron supplementation efficiently restored iron status but did not improve the humoral or cellular immune response against SARS-CoV-2 after three vaccinations.