A syndrome of dysregulated systemic immune overactivation has been described in patients with COVID-19. Initially a cytokine storm paradigm was proposed, however subsequently, it has been shown that systemic concentrations of inflammatory cytokines, although elevated in patients with severe COVID-19, are not as high as has been reported in patients with other causes of the acute respiratory distress syndrome (ARDS).2Sinha P Calfee CS Cherian S et al.Prevalence of phenotypes of acute respiratory distress syndrome in critically ill patients with COVID-19: a prospective observational study. Despite this, data to support the use of immunomodulatory therapies, such as corticosteroids3Horby P Lim WS Emberson JR et al.Dexamethasone in hospitalized patients with Covid-19. and interleukin-6 (IL-6) receptor antagonists,4Gordon AC Mouncey PR Al-Beidh F et al.Interleukin-6 receptor antagonists in critically ill patients with Covid-19. in patients critically ill with COVID-19 have emerged. With this in mind, it might seem plausible that the direct removal of circulating inflammatory mediators could offer a way to reset the cytokine milieu and provide clinical benefit.In an important test of this hypothesis, in The Lancet Respiratory Medicine, Alexander Supady and colleagues5Supady A Weber E Rieder M et al.Cytokine adsorption in patients with severe COVID-19 pneumonia requiring extracorporeal membrane oxygenation (CYCOV): a single centre, open-label, randomised, controlled trial. examined the efficiency of extracorporeal cytokine adsorption for the removal of IL-6. In their single-centre, pilot trial, the authors randomly allocated patients with COVID-19-related ARDS receiving venovenous extracorporeal membrane oxygenation (ECMO) to cytokine adsorption (n=17) for 72 h. Those not undergoing cytokine adsorption on ECMO served as controls (n=17) and the serum IL-6 concentrations were compared at 72 h. Mediator removal is concentration dependent and cytokine adsorption removes not only proinflammatory and anti-inflammatory mediators but many other biological substances (up to 55 kDa) as well.There was no difference in the primary outcome (serum IL-6 concentrations measured at 72 h) between groups. By day 30, 13 (76%) of 17 patients in the intervention group and three of (18%) 17 in the control group had died—a marked difference in mortality favouring the control group. The authors did several exploratory post-hoc analyses in light of this finding, yet they could not establish specific causative mechanisms implicating harm from the intervention itself. Pending further evidence, as Supady and colleagues note, the use of cytokine adsorption in patients receiving ECMO for COVID-19-related ARDS should be confined to research studies. Even before this trial, the Extracorporeal Life Support Organization's COVID-19 guidelines did not recommend extracorporeal cytokine adsorption outside the context of a clinical trial.6Badulak J Antonini MV Stead CM et al.ECMO for COVID-19: Updated 2021 guidelines from the extracorporeal life support organization (ELSO). The authors have stopped recruitment for their multicentre version of this trial (CYCOV-II; NCT04385771) and it might be challenging to establish equipoise for future trials in a similar setting.Why would such a plausible intervention turn out not only to be inefficient but also potentially harmful? First, the inability to remove IL-6 is unexpected, although smaller studies in the past have reported similar findings.7Schädler D Pausch C Heise D et al.The effect of a novel extracorporeal cytokine hemoadsorption device on IL-6 elimination in septic patients: a randomized controlled trial. There were no reported technical issues that might have led to reduced IL-6 clearance. Second, the median IL-6 concentration at baseline was 357·0 pg/mL, which is substantially lower when compared with studies that reported better IL-6 clearance8Friesecke S Träger K Schittek GA et al.International registry on the use of the CytoSorb® adsorber in ICU patients : Study protocol and preliminary results. and concentration dependent clearance might be at play. Notwithstanding this, both groups had reductions in IL-6 concentrations at 72 h (median, baseline [72 h], 357·0 pg/mL [98·6 pg/mL] vs 289·0 pg/mL [112·0 pg/mL]). It is unclear whether the reductions are due to the effects of ventilation strategies during ECMO, treatment effects of other therapies, or potential cytokine sequestration in the ECMO circuit. It might also simply be related to improvements seen over time, as reported previously.9McAuley DF Laffey JG O'Kane CM Perkins GD Mullan B Trinder TJ et al.Simvastatin to reduce pulmonary dysfunction in patients with acute respiratory distress syndrome: the HARP-2 RCT. Third, timing of treatment initiation and patient inclusion criteria in this trial might be pertinent. It might be too late to see a benefit from cytokine adsorption when initiated in patients already receiving ECMO. In contrast, IL-6 receptor antagonists were shown to be more effective when critically ill patients were treated early4Gordon AC Mouncey PR Al-Beidh F et al.Interleukin-6 receptor antagonists in critically ill patients with Covid-19. (within 24 h after commencing organ support in the intensive care unit). Fourth, the patients in this study exhibited highly variable IL-6 concentrations at baseline and it is difficult to ascertain whether outcomes would be different if the trial had been enriched with patients having higher IL-6 concentrations, for instance greater than 1000 pg/mL. This highlights the need to develop point of care assays for cytokines such as IL-6, which is being tested in the ongoing point-of-care assay to identify phenotypes in the ARDS (PHIND) trial (NCT04009330). Fifth, systemic cytokine concentrations might be less relevant, and it is possible that local pulmonary inflammation could be a more useful indicator of which patients will benefit from cytokine adsorption. Lastly, initiation of cytokine adsorption might have unknown interactions with other immunomodulatory therapies, such as corticosteroids and IL-6 receptor antagonists. The effect of cytokine adsorption on the concentrations of these vital disease modifying drugs is unclear and there are reports of suboptimal antimicrobial concentrations during cytokine adsorption.10Zoller M Döbbeler G Maier B Vogeser M Frey L Zander J Can cytokine adsorber treatment affect antibiotic concentrations? A case report.

In the end, the cause of the apparent harm of the intervention is unknown. It is important to reiterate that, no matter how compelling the mechanisms supporting a proposed intervention, the intervention must still be subjected to a well designed clinical trial. The authors should be commended for doing precisely that. The study by Supady and colleagues, clearly highlights the potential risks of cytokine adsorption in patients receiving ECMO for COVID-19-related ARDS and the importance of minimising iatrogenic harm by testing promising interventions in clinical trials.

KS reports no conflicts of interest. DFM reports personal fees for consultancy from GlaxoSmithKline, Boehringer Ingelheim, Novartis, Eli Lilly, and Bayer for ARDS, and from sitting on a data monitoring and ethics committee for a trial done by Vir Biotechnology; has a patent issued to his institution for a treatment for ARDS; and is a Director of Research for the Intensive Care Society and NIHR EME Programme. In addition, his institution has received grants from the UK National Institute for Health Research, Wellcome Trust, Innovate UK, and others for ARDS and respiratory failure research. DB receives research support from ALung Technologies and has been on the medical advisory boards for Baxter, Abiomed, Xenios, and Hemovent.

References1.

Cytokine storm.

N Engl J Med. 383: 2255-22732.Sinha P Calfee CS Cherian S et al.

Prevalence of phenotypes of acute respiratory distress syndrome in critically ill patients with COVID-19: a prospective observational study.

Lancet Respir Med. 8: 1209-12183.Horby P Lim WS Emberson JR et al.

Dexamethasone in hospitalized patients with Covid-19.

N Engl J Med. 384: 693-7044.Gordon AC Mouncey PR Al-Beidh F et al.

Interleukin-6 receptor antagonists in critically ill patients with Covid-19.

N Engl J Med. 384: 1491-15025.Supady A Weber E Rieder M et al.

Cytokine adsorption in patients with severe COVID-19 pneumonia requiring extracorporeal membrane oxygenation (CYCOV): a single centre, open-label, randomised, controlled trial.

Lancet Respir Med. ()6.Badulak J Antonini MV Stead CM et al.

ECMO for COVID-19: Updated 2021 guidelines from the extracorporeal life support organization (ELSO).

ASAIO J. ()7.Schädler D Pausch C Heise D et al.

The effect of a novel extracorporeal cytokine hemoadsorption device on IL-6 elimination in septic patients: a randomized controlled trial.

PLoS One. 12e01870158.Friesecke S Träger K Schittek GA et al.

International registry on the use of the CytoSorb® adsorber in ICU patients : Study protocol and preliminary results.

Med Klin Intensivmed Notfmed. 114: 699-7079.McAuley DF Laffey JG O'Kane CM Perkins GD Mullan B Trinder TJ et al.

Simvastatin to reduce pulmonary dysfunction in patients with acute respiratory distress syndrome: the HARP-2 RCT.

Efficacy Mech Eval. 5 ()10.Zoller M Döbbeler G Maier B Vogeser M Frey L Zander J

Can cytokine adsorber treatment affect antibiotic concentrations? A case report.

J Antimicrob Chemother. 70: 2169-2171Article InfoPublication HistoryIdentification

DOI: https://doi.org/10.1016/S2213-2600(21)00207-1

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