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.
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.
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
-
- 3,805
- views
-
- 567
- downloads
-
- 136
- 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
The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been increasing worldwide. Since gut-derived bacterial lipopolysaccharides (LPS) can travel via the portal vein to the liver and play an important role in producing hepatic pathology, it seemed possible that (1) LPS stimulates hepatic cells to accumulate lipid, and (2) inactivating LPS can be preventive. Acyloxyacyl hydrolase (AOAH), the eukaryotic lipase that inactivates LPS and oxidized phospholipids, is produced in the intestine, liver, and other organs. We fed mice either normal chow or a high-fat diet for 28 weeks and found that Aoah-/- mice accumulated more hepatic lipid than did Aoah+/+ mice. In young mice, before increased hepatic fat accumulation was observed, Aoah-/- mouse livers increased their abundance of sterol regulatory element-binding protein 1, and the expression of its target genes that promote fatty acid synthesis. Aoah-/- mice also increased hepatic expression of Cd36 and Fabp3, which mediate fatty acid uptake, and decreased expression of fatty acid-oxidation-related genes Acot2 and Ppara. Our results provide evidence that increasing AOAH abundance in the gut, bloodstream, and/or liver may be an effective strategy for preventing or treating MASLD.
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease in a variety of animal models. However, clinical trials of PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations of antibodies identified using protein-immunized animal systems and required extensive engineering to optimize binding and/or reduce immunogenicity. Of note, PA infections are common in people with cystic fibrosis (pwCF), who are generally believed to mount normal adaptive immune responses. Here, we utilized a tetramer reagent to detect and isolate PcrV-specific B cells in pwCF and, via single-cell sorting and paired-chain sequencing, identified the B cell receptor (BCR) variable region sequences that confer PcrV-specificity. We derived multiple high affinity anti-PcrV monoclonal antibodies (mAbs) from PcrV-specific B cells across three donors, including mAbs that exhibit potent anti-PA activity in a murine pneumonia model. This robust strategy for mAb discovery expands what is known about PA-specific B cells in pwCF and yields novel mAbs with potential for future clinical use.