Presence of rare potential pathogenic variants in subjects under 60 years old with very severe or fatal COVID-19

Background/Objectives: Genetic variants affecting host defense against pathogens may help explain COVID-19 fatal outcomes. Our aim was to identify rare genetic variants related to COVID-19 severity in a selected group of patients under 60 years who required intubation or resulting in death. Method(s): Forty-four very severe COVID-19 patients were selected from the Spanish STOP-Coronavirus cohort, which comprises more than 3,500 COVID-19 patients. Genotype was performed by whole exome sequencing and variants were selected by using a gene panel of 867 candidate genes (immune response, primary immunodeficiencies or coagulation, among other). Variants were filtered, priorized and their potential pathogenicity was assessed following ACGM criteria. Result(s): We detected 44 different variants of interest, in 29 different patients (66%). Some of these variants were previously described as pathogenic (26%). Mostly, the candidate variants were located in genes related to immune response (38%), congenital disorders of glycosylation (14%) or damaged DNA binding genes (9%). A network analysis, showed three main components, consisting of 25 highly interconnected genes related to immune response and two additional networks enriched in carbohydrate metabolism and in DNA metabolism and repair processes. Conclusion(s): The variants identified affect different, but interrelated, functional pathways such as immune response and glycosylation. Further studies are needed for confirming the ultimate role of the new candidate genes described in the present study on COVID-19 severity.

Immunosuppression minimization in kidney transplant recipients hospitalized for COVID-19

BACKGROUND AND AIMS: Immunosuppressed patients such as kidney transplant recipients (KTs) have increased mortality risk in the setting of coronavirus disease 2019 (COVID-19). The role and management of chronic immunosuppressive therapies during COVID-19 must be characterized. METHOD: Herein, we report the follow-up of a cohort of 47 KTs admitted at two Spanish Kidney Transplant Units who survived COVID-19. The impact of the management of immunosuppression during COVID-19 on graft function and immunologic events was evaluated. RESULTS: At least one immunosuppressive agent was withdrawn in 83% of patients, with antimetabolites being the most frequent. Steroids were generally not stopped and the dose was even increased in 15% of patients as part of the treatment of COVID-19. Although immunosuppressive drugs were suspended during a median time of 17 days, no rejection episodes neither de novo donor specific antibodies were observed up to 3 months after discharge, and no significant changes occurred in calculated panel reactive antibodies. Acute graft dysfunction was common (55%) and the severity was related to tacrolimus trough levels, which were higher in patients receiving antivirals. At the end of follow-up, all patients recovered baseline kidney function. CONCLUSION: Our observational study suggests that immunosuppression in KTs hospitalized due to COVID-19 could be safely minimized.

Inmune status on haemodialysis pattients affected with covid19 infection

BACKGROUND AND AIMS: End-stage renal disease patients on haemodialysis (HD) seem more likely to develop severe COVID19 disease. Over the course of COVID disease, we observed a poor tolerance to HD sessions with a marked tendency of clinical deterioration over them. The objective is to evaluate changes on immunological system over HD session on patients affected with COVID19 compared with patients without COVID19. METHOD: Fourteen HD patients were studied including 9 confirmed COVID19 infection and 5 healthy controls. Predialysis and postdialysis blood samples were compared to study alterations on immune status. We identified cytoKines by Luminex (CCL2, CXCL10, IL1Ra, IL10, IL12p70, TNFa, IL17Ra, IL6, IL7) and adaptive lymphocyte subsets (CD4/CD8 naïve, CD4/CD8 MC, CD4/CD8 MP, CD19, CD56). Monocyte subsets (CD14+CD16-, CD14+CD16+, CD14-CD16+) were detected from peripheral blood mononuclear cells (PBMC), as well as immune activation (CD11b, HLA-DR, CD86) and migration factors (CCR2, CCR5). The supernatant of isolated CD14+ cells after 4-hour stimulation with LPS where analysed by Luminex to measure cytokines (CCL2, CXCL10, GM-CSF, IL10, IL12p70, IL17Ra, IL6, IL7, TNFa). RESULTS: Patients with COVID19 presented predialysis: (1) higher plasmatic levels of IL12p70, TNFa e IL7, (2) lymphopenia and neutrophilia, (3) higher percentage of intermediate monocytes and lower of non-classical, (4) lower membrane expression of CCR2, HLA-DR y CD86 over Cd14+ cells, and (5) higher production of CCL2, GMCSF, IL10, IL12p70 y IL17Ra by LPS stimulated monocytes compared with patients without COVID19. When analysed the fold-change between pre and postdialysis values, patients with COVID19 infection present a: (a) higher plasmatic levels of IL6, IL1Ra, CCL2 e CXCL10, (b) reductions of total lymphocites, (c) higher membrane expression of CCR2, CD33 y CD86 on CD14+ cells, and (d) higher production of TNFa, GM-CSF, IL10, IL17, IL6 e IL7 by LPS stimulated monocytes compared with patients without COVID19. No differences on lymphocite subset were found. CONCLUSION: The clinical deterioration on COVID19 infected patients over HD session could be related with monocyte activation and pro-inflammatory cytokines secretion.