A guide to immunotherapy for COVID-19 van de Veerdonk, Frank L; Giamarellos-Bourboulis, Evangelos; Pickkers, Peter ...
Nature medicine,
01/2022, Volume:
28, Issue:
1
Journal Article
Peer reviewed
Open access
Immune dysregulation is an important component of the pathophysiology of COVID-19. A large body of literature has reported the effect of immune-based therapies in patients with COVID-19, with some ...remarkable successes such as the use of steroids or anti-cytokine therapies. However, challenges in clinical decision-making arise from the complexity of the disease phenotypes and patient heterogeneity, as well as the variable quality of evidence from immunotherapy studies. This Review aims to support clinical decision-making by providing an overview of the evidence generated by major clinical trials of host-directed therapy. We discuss patient stratification and propose an algorithm to guide the use of immunotherapy strategies in the clinic. This will not only help guide treatment decisions, but may also help to design future trials that investigate immunotherapy in other severe infections.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Dexamethasone improves the survival of COVID-19 patients in need of supplemental oxygen therapy. Although its broad immunosuppressive effects are well-described, the immunological ...mechanisms modulated by dexamethasone in patients hospitalized with COVID-19 remain to be elucidated.
Objective
We combined functional immunological assays and an omics-based approach to investigate the
in vitro
and
in vivo
effects of dexamethasone in the plasma and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients.
Methods
Hospitalized COVID-19 patients eligible for dexamethasone therapy were recruited from the general care ward between February and July, 2021. Whole blood transcriptomic and targeted plasma proteomic analyses were performed before and after starting dexamethasone treatment. PBMCs were isolated from healthy individuals and COVID-19 patients and stimulated with inactivated SARS-CoV-2
ex vivo
in the presence or absence of dexamethasone and transcriptome and cytokine responses were assessed.
Results
Dexamethasone efficiently inhibited SARS-CoV-2-induced
in vitro
expression of chemokines and cytokines in PBMCs at the transcriptional and protein level. Dexamethasone treatment in COVID-19 patients resulted in down-regulation of genes related to type I and II interferon (IFN) signaling in whole blood immune cells. In addition, dexamethasone attenuated circulating concentrations of secreted interferon-stimulating gene 15 (ISG15) and pro-inflammatory cytokines and chemokines correlating with disease severity and lethal outcomes, such as tumor necrosis factor (TNF), interleukin-6 (IL-6), chemokine ligand 2 (CCL2), C-X-C motif ligand 8 (CXCL8), and C-X-C motif chemokine ligand 10 (CXCL10). In PBMCs from COVID-19 patients that were stimulated
ex vivo
with multiple pathogens or Toll-like receptor (TLR) ligands, dexamethasone efficiently inhibited cytokine responses.
Conclusion
We describe the anti-inflammatory impact of dexamethasone on the pathways contributing to cytokine hyperresponsiveness observed in severe manifestations of COVID-19, including type I/II IFN signaling. Dexamethasone could have adverse effects in COVID-19 patients with mild symptoms by inhibiting IFN responses in early stages of the disease, whereas it exhibits beneficial effects in patients with severe clinical phenotypes by efficiently diminishing cytokine hyperresponsiveness.
Disease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of ...disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression, and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using machine learning classifiers trained to distinguish disease-associated from dispensable genes, we classify 247 genes, including 115 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants.
Non-typhoidalSalmonellae (NTS) are virulent bacteria that commonly cause gastroenteritis. However, less than 5% of patients infected with NTS develop bacteraemia and metastatic foci of infection. ...Mortality remains high, despite appropriate use of antibiotic therapy. We present three cases to demonstrate that immunodeficiency - and T-cell dysfunction in particular - is a major risk factor for NTS bacteraemia. All three patients presented with fever and general malaise, while none of them had symptoms of gastroenteritis. Blood cultures revealed the presence of Salmonella enteritidis, but stool cultures were negative. All three patients were diagnosed with vascular infection, for which they were treated with a combination of surgery and antibiotics. The efficiency of NTS clearance depends greatly on successful antigen presentation to T-cells. T-cell dysfunction contributes to the development of bacteraemia. These cases emphasise the importance of recognising extraintestinal complications of NTS infection in immunocompromised patients, particularly those associated with T-cell dysfunction.
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