An open label trial of anakinra to prevent respiratory failure in COVID-19
Abstract
Background It was studied if early suPAR-guided anakinra treatment can prevent severe respiratory failure (SRF) of COVID-19.
Methods 130 patients with suPAR ≥6 ng/ml were assigned to subcutaneous anakinra 100mg once daily for 10 days. Primary outcome was SRF incidence by day 14 defined as any respiratory ratio below 150 mmHg necessitating mechanical or non-invasive ventilation. Main secondary outcomes were 30-day mortality and inflammatory mediators; 28-day WHO-CPS was explored. Propensity-matched standard-of care comparators were studied.
Results 22.3% with anakinra treatment and 59.2% comparators (hazard ratio, 0.30; 95%CI, 0.20-0.46) progressed into SRF; 30-day mortality was 11.5% and 22.3% respectively (hazard ratio 0.49; 95% CI 0.25-0.97). Anakinra was associated with decrease in circulating interleukin (IL)-6, sCD163 and sIL2-R; IL-10/IL-6 ratio on day 7 was inversely associated with SOFA score; patients were allocated to less severe WHO-CPS strata.
Conclusions Early suPAR-guided anakinra decreased SRF and restored the pro-/anti-inflammatory balance.
Trial Registration: ClinicalTrials.gov, NCT04357366
Data availability
Data of this submission are anticipated to be part of a submission package to the European Medicines Agency for the request of approval of Anakinra for the management of COVID-19 guided by the biomarker suPAR. Once this is finalized, the data will be made publicly available upon request. Requests will require signing contract with the sponsor of the study which is the Hellenic Institute for the Study of Sepsis. The responsible official is Ms Leda Efstratiou who is the DPO responsible for GDPR. Interested researchers should contact Ms Efstratiou at le.efstrat@gmail.com and headed@sepsis.gr to request access to the data.
Article and author information
Author details
Funding
Hellenic Institute for the Study of Sepsis (NA)
- Evangelos J Giamarellos-Bourboulis
Technomar Shipping Inc (NA)
- Evangelos J Giamarellos-Bourboulis
Swedish Orphan Biovitrum AB (NA)
- Evangelos J Giamarellos-Bourboulis
Horizon 2020 (RISKinCOVID)
- Evangelos J Giamarellos-Bourboulis
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Arduino A Mangoni, Flinders Medical Centre, Australia
Ethics
Human subjects: Approved in Greece by National Ethics Committee approval 38/20; National Organization for Medicines approval ISO 28/20.Written informed consent was provided by the patient or legal representative before screening.
Version history
- Received: December 29, 2020
- Accepted: March 4, 2021
- Accepted Manuscript published: March 8, 2021 (version 1)
- Version of Record published: April 9, 2021 (version 2)
Copyright
© 2021, Kyriazopoulou et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,685
- views
-
- 548
- downloads
-
- 122
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Immunology and Inflammation
Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as arachidonate 5-lipoxygenase (ALOX5) and ALOX5 activating protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6 days training, they exhibit enhanced TNF-α and IL-6 production to lipopolysaccharide (LPS). Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients.
-
- Cancer Biology
- Immunology and Inflammation
Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibitors. However, despite robust preclinical anticancer efficacy, DHODH inhibitors have shown limited single-agent activity in phase 1 and 2 clinical trials. Therefore, novel combination therapy strategies are necessary to realize the potential of these drugs. To search for therapeutic vulnerabilities induced by DHODH inhibition, we examined gene expression changes in cancer cells treated with the potent and selective DHODH inhibitor brequinar (BQ). This revealed that BQ treatment causes upregulation of antigen presentation pathway genes and cell surface MHC class I expression. Mechanistic studies showed that this effect is (1) strictly dependent on pyrimidine nucleotide depletion, (2) independent of canonical antigen presentation pathway transcriptional regulators, and (3) mediated by RNA polymerase II elongation control by positive transcription elongation factor B (P-TEFb). Furthermore, BQ showed impressive single-agent efficacy in the immunocompetent B16F10 melanoma model, and combination treatment with BQ and dual immune checkpoint blockade (anti-CTLA-4 plus anti-PD-1) significantly prolonged mouse survival compared to either therapy alone. Our results have important implications for the clinical development of DHODH inhibitors and provide a rationale for combination therapy with BQ and immune checkpoint blockade.