key: cord-0722755-o3cxjm5d
authors: Schmidt, Julius J; Borchina, Dan Nicolae; van´t Klooster, Mariet; Bulhan-Soki, Khalida; Okioma, Reuben; Herbst, Larissa; Rodríguez, Diego Sandoval; Premužić, Vedran; Büttner, Stefan; Bader, Birgit; Serednicki, Wojciech; Zasada, Ewa; Schmitz, Michael; Quabach, Ralf A; Hrincheva, Maria; Fühner, Thomas; Kielstein, Jan T
title: Interim-analysis of the COSA (COVID-19 patients treated with the Seraph(®) 100 Microbind(®) Affinity filter) registry
date: 2021-12-07
journal: Nephrol Dial Transplant
DOI: 10.1093/ndt/gfab347
sha: 1c49c4d8c7a89abd300fe6b99be290d9ff343451
doc_id: 722755
cord_uid: o3cxjm5d

BACKGROUND: The Seraph(®)100 Microbind Affinity Blood Filter(®) is a hemoperfusion device that is licensed for the reduction of pathogens, including several viruses, in the blood. It received Emergency Use Authorization (EUA) for the treatment of severe coronavirus disease 2019 (COVID-19) by the FDA. Several studies have shown that the blood viral load of SARS-CoV-2 correlates with adverse outcomes and removal of the nucleocapsid of the SARS-CoV-2 virus by the Seraph(®)100 has been recently demonstrated. The aim of this registry was to evaluate safety and efficacy of Seraph(®)100 treatment for COVID-19 patients. METHODS: Twelve hospitals from six countries representing two continents documented patient and treatment characteristics as well as outcome parameters without reimbursement. Additionally, mortality and safety results of the device were reported. One hundred-and-two treatment sessions in 82 patients were documented in the registry. Four patients were excluded from mortality analysis due to incomplete outcome data, which were available in the other 78 patients. RESULTS: Overall, a 30-day mortality rate of 46.2% in the 78 patients with complete follow up was reported. Median treatment time was 5.00 [4.00–13.42] h. and 43.1% of the treatments were performed as hemoperfusion only. Adverse events of the Seraph(®)100 treatment were reported in 8.8% of the 102 treatments and represented premature end of treatment due to circuit failure. Patients that died were treated later in their ICU stay and onset of COVID symptoms. They also had higher ferritin levels. Multivariate Cox regression revealed that delayed Seraph(®)100 treatment after ICU admission (>60 hours) as well as bacterial superinfection were associated with mortality. While average predicted mortality rate according to SOFA score in ICU patients was 56.7% the observed mortality was 50.7%. In non-ICU patients 4C-Score average predicted a mortality rate of 38.0% while the observed mortality rate was 11.1% CONCLUSIONS: The treatment of COVID-19 patients with Seraph(®)100 is well tolerated and the circuit failure rate was lower than previously reported for KRT in COVID-19 patients. Mortality corelated with late initiation of Seraph treatment after ICU admission and bacterial superinfection infection. Compared to predicted mortality according to 4C-Score and SOFA Score, mortality of Seraph(®)100 treated patients reported in the registry was lower.

and encouraging preliminary data using recombinant interleukin-1 receptor antagonist, (4) none of the many repurposed drugs that had been suggested for the treatment of COVID-19 have substantiated its therapeutic effectiveness in randomized prospective trials (5) (6) (7) (8) . Both successful antibody-mediated strategies, the combination of the monoclonal antibodies casirivimab and imdevimab (9) as well as the pansarbecovirus monoclonal antibody sotrovimab, (10) 

Of the 102 entered datasheets in the registry, 20 represented repeated Seraph ® 100 treatments.

After exclusion of incompletely documented patients (n=4), partly due to ongoing ICU treatment, 78 patients could be analyzed ( Figure 1 ). Table 3) .

Adverse events were reported in 9 (8.8 %) of the 102 treatments. Circuit failure was the most commonly reported adverse event, occurring in 9 of the treatments. Other side effects also occurred within the group of 9 patients included hypotension in two patients and shivering and fever in one patient. No adverse event was declared as serious ( Table 2) . 

1996 to evaluate organ failure, can predict the severity and outcome of diseases such as sepsis (28). It has also been of predictive value in COVID-19 with an odds ratio of 5.56 in an in an early report from China (29). A late report in in patients with COVID-19 pneumonia receiving oxygen therapy for 4 hours or longer, before undergoing endotracheal intubation, showed poor performance of the SOFA score to discriminate death from survival, and SOFA score was found to be even inferior than using age alone (30).

In non-ICU patients 4C-Score average predicted a mortality rate of 38.0 % while the observed mortality rate Seraph ® 100 treated patients was 11.1 %. However, the 4C-Score was calculated at the day of Seraph 100 treatment and not during hospital admission, for which the score was originally validated. Therefore, our observed differences in mortality between calculated and observed mortality must be interpreted with caution.

Treatment with Seraph ® 100 was initiated earlier after the onset of symptoms in the survivors than in those who succumbed. Also, time from ICU admission to Seraph ® 100 treatment was shorter in the survivors that in the non-survivors. Mortality in ICU patients that started Seraph ® 100 treatment within 60 hours of ICU admission was 34.5 % (predicted 51.7 %) and

almost 50 % lower than in those patients in which Seraph ® 100 treatment was initiated after more than 60 hours in the ICU (Figure 2) . This is reminiscent of data in patient with AKI in the ICU undergoing KRT. Late start of KRT (relative to ICU admission) was associated with greater mortality, irrespective of urea levels (31).

Early reports from China showed that a fulminant inflammatory response to the viral infection correlates with disease severity (32). In our cohort ferritin was the only inflammatory marker that was significantly different between survivors and non-survivors which is in line with the

importance of ferritin as the only inflammatory marker in a score predicting mortality within 14 days after intubation (33). However, in multivariate Cox regression analysis, ferritin levels

were not significantly associated with mortality in our study.

A single center analysis showed that >30% of hemofilters failed < 9 hours due to clotting and the median circuit life was 21 hours (34). In our analysis, filter clotting was as low as 8.8 % although more than half of the treatments were performed in conjunction with renal replacement therapy.

The inherent limitation of a registry in comparison to a prospective randomized trial is the lack of a control group. Nonetheless the collection of data will in our view help to focus future prospective randomized trials in terms of inclusion / exclusion criteria as well as variables to investigate. Ongoing prospective clinical trials in Europe (NCT04547257) and the US (NCT04606498) will further clarify the role of the Seraph in the treatment of COVID-19

patients.

In conclusion, treatment of critically ill patients with the Seraph ® 100 was well tolerated with a low rate of reported clotting events. Early initiation of treatment after ICU admission was associated with increased survival. Reported mortality was lower than expected according to 

Not applicable.

The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request. Kaplan-Meier analysis of survival in patients stratified for ICU admission < and > 60 hours during 30 days (p log-rank test < 0.015).

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We thank Ms. Alina Siegert for her logistical support.