key: cord-270388-nozh463l authors: Damiani, M.; Gandini, L.; Landi, F.; Fabretti, F.; Gritti, G.; Riva, I. title: Extracorporeal Cytokine Hemadsorption in Severe COVID-19 Respiratory Failure date: 2020-06-29 journal: nan DOI: 10.1101/2020.06.28.20133561 sha: doc_id: 270388 cord_uid: nozh463l Despite the extracorporeal cytokine hemadsorption device CytoSorb was granted FDA emergency approval for critically ill COVID19 patients, to our knowledge no published studies are currently available to support its use. This manuscript reports the experience of the use of CytoSorb during COVID19 pandemic in Bergamo, Italy. In our pilot study, eleven COVID19 patients requiring invasive mechanical ventilation for a rapidly progressive ARDS were treated with 24 to 48 hours of extracorporeal cytokine hemadsorption. Respiratory and laboratory parameters, including a full set of inflammatory cytokines, were evaluated at different time points. A significant but transient reduction of the hyperinflammatory status was observed, along with the amelioration of the clinical and respiratory parameters. To the Editor, Nearly 20% of patients infected by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) experience a severe disease requiring admission to intensive care unit (ICU) with mortality rates up to 26% of the cases. 1 2 Hyper-inflammatory activation characterized by immune cell infiltration and elevated levels of cytokines as interleukin (IL)-6, IL-8 and C-reactive protein (CRP) was reported as the main mechanism leading to critical illness and severe acute respiratory distress syndrome (ARDS). 3 Thus, targeting the cytokine storm may represent a promising therapeutic strategy. While the use of monoclonal antibodies targeting the IL-6 pathway was reported to improve outcome, a significant increase of bacterial infections has been observed. 4 An alternative treatment able to reduce circulating cytokines in critically ill patients is CytoSorb (Aferetica srl, Italy), a device containing adsorbent polymer beads designed to irreversibly remove cytokines currently used for septic shock and other conditions where elevated levels of cytokines are present. 5 Along with the beneficial effect on system inflammation, CytoSorb can be easily integrated with all extracorporeal circulation systems, as continuous renal replacement therapy (CRRT) or ExtraCorporeal Membrane Oxygenation (ECMO). Despite the lack of published results, based on bench performance testing and reported clinical experience, CytoSorb was granted FDA emergency approval for critically ill SARS-CoV-2 patients on April 10, 2020. 6 In this report we present the laboratory and clinical outcome of Corona Virus Disease 2019 (COVID19) patients treated with CytoSorb at Papa Giovanni XXIII Hospital, Bergamo, Italy. The study was approved by the Ethic Committee and patients, or their legal representative, provided either verbal or written consent to participate in the study. Clinical data were gathered from the electronic charts. Inflammatory cytokines including IL-1β, IL-6, IL-8, IL-10 IL-12p70 and tumor necrosis factor (TNF)-α were dosed in a single serum sample by flow cytometry (BD CBA Human Inflammatory Cytokines Kit, BD Biosciences, USA). Non-parametric multiple comparison Kurskalis-Wallis tests All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 29, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 29, 2020. . https://doi.org/10.1101/2020.06.28.20133561 doi: medRxiv preprint C-reactive protein (CRP) levels and respiratory parameters including the PaO2/FiO2 ratio (P/F) were assessed daily. Consistent with the trend observed for IL-6, a significant drop of CRP median levels was observed starting from 2 days after treatment and for the subsequent 4 days, followed by a new increase (Figure 1 ). Median P/F value at enrolment was 103 (IQR 88-133), consistent with a moderate to severe ARDS. The decrease in the inflammatory status was associated with a progressive improvement in the respiratory function, with a significant increase in P/F from the first day after end of the therapy (Figure 1 ). No unexpected adverse events were observed with CytoSorb use. After a median follow-up of 16 days (range 6-30 days), 2 patients died (18%) after 6 and 16 days from enrollment, and 9 are still alive. In 3 patients weaning was completed with extubation at day 14, 15 and 27 from enrollment. Six patients required percutaneous tracheostomy to achieve respiratory weaning. All 9 patients were discharged from ICU after a median of 25 days (range 11-52). In this study we report for the first time that CytoSorb treatment for 24-48 hours significantly reduces IL-6 levels resulting in a beneficial effect on systemic inflammation in the subsequent days. However, the persistence of significant levels of IL-6 and CRP after treatment and their increase at one week suggest that a more prolonged treatment is required to control SARS-CoV-2 hyperinflammatory status. Since no specific guidelines were available at the time, CytoSorb was used empirically based on previous experience in septic shock. However, the results support the proposed CytoSorb use with 72 hours long treatment with 4 adsorbers. With the limitation of the small sample size, CytoSorb proved to be safe and a clinical amelioration was observed in most of the treated patients despite the severity of the disease. Further studies are required to assess if CytoSorb can improve the clinical outcome of critically ill patients. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 29, 2020. . https://doi.org/10.1101/2020.06.28.20133561 doi: medRxiv preprint . All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 29, 2020. Expert recommendations on blood purification treatment protocol for patients with severe COVID-19. Chronic Dis Baseline Characteristics and Outcomes of 1591 Patients Infected with SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support Hemoadsorption by CytoSorb in septic patients: A case series Food and Drug Administration. CytoSorb ® 300 mL Device Approved by FDA for Emergency Treatment of COVID-19