ORIGINAL RESEARCH published: 10 January 2022 doi: 10.3389/fmed.2021.779038 Cytokine Hemoadsorption as Rescue Therapy for Critically Ill Patients With SARS-CoV-2 Pneumonia With Severe Respiratory Failure and Hypercytokinemia Juan Carlos Ruiz-Rodríguez 1,2,3 , Luis Chiscano-Camón 1,2,3*, Adolf Ruiz-Sanmartin 1,2 , Clara Palmada 1,2 , Erika Paola Plata-Menchaca 1,2 , Clara Franco-Jarava 4 , Marcos Pérez-Carrasco 1,2 , Manuel Hernández-González 4 and Ricard Ferrer 1,2,3 1 Department of Intensive Care, Vall d’Hebron University Hospital, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain, 2 Shock, Organ Dysfunction and Resuscitation Research Group, Vall d’Hebron Research Institute (VHIR), Vall Edited by: d’Hebron University Hospital, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain, 3 Departament de Medicina, Luo Zhe, Universitat Autonoma de Barcelona, Barcelona, Spain, 4 Department of Immunology, Vall d’Hebron Hospital Universitari, Vall Fudan University, China d’Hebron Barcelona Hospital Campus, Barcelona, Spain Reviewed by: Talha Bin Emran, Begum Gulchemonara Trust Introduction: A dysregulated inflammatory response, known as “cytokine storm”, plays University, Bangladesh an important role in the pathophysiology of coronavirus 2019 disease (COVID-19). Denise Battaglini, Ospedale San Martino (IRCCS), Italy Identifying patients with a dysregulated inflammatory response and at high risk for severe *Correspondence: respiratory failure, organ dysfunction, and death is clinically relevant, as they could benefit Luis Chiscano-Camón from the specific therapies, such as cytokine removal by hemoadsorption. This study lchiscano@vhebron.net aimed to evaluate cytokine hemoadsorption as rescue therapy in critically ill patients Specialty section: with SARS-CoV-2 pneumonia, severe respiratory failure refractory to prone positioning, This article was submitted to and hypercytokinemia. Intensive Care Medicine and Anesthesiology, Methods: In this single center, observational and retrospective study, critically a section of the journal ill patients with SARS-CoV-2 pneumonia, severe acute respiratory failure, and Frontiers in Medicine hypercytokinemia were analyzed. All the patients underwent cytokine hemoadsorption Received: 17 September 2021 Accepted: 23 November 2021 using CytoSorb® (Cytosorbents Europe, Berlin, Germany). The indication for treatment Published: 10 January 2022 was acute respiratory failure, inadequate clinical response to the prone position, Citation: and hypercytokinemia. Ruiz-Rodríguez JC, Chiscano-Camón L, Results: Among a total of 343 patients who were admitted to the intensive care unit (ICU) Ruiz-Sanmartin A, Palmada C, Paola due to SARS-CoV-2 infection between March 3, 2020 and June 22, 2020, six patients Plata-Menchaca E, Franco-Jarava C, Pérez-Carrasco M, received rescue therapy with cytokine hemoadsorption. All the patients needed invasive Hernández-González M and Ferrer R mechanical ventilation and prone positioning. A significant difference was found in the (2022) Cytokine Hemoadsorption as pre- and post-treatment D-dimer (17,868 mcg/ml [4,196–45,287] vs. 4,488 mcg/ml Rescue Therapy for Critically Ill Patients With SARS-CoV-2 [3,166–17,076], p = 0.046), C-reactive protein (12.9 mg/dl [10.6] vs. 3.5 mg/dl [2.8], Pneumonia With Severe Respiratory p = 0.028), ferritin (1,539 mcg/L [764–27,414] vs. 1,197 ng/ml [524–3,857], p = 0.04) Failure and Hypercytokinemia. Front. Med. 8:779038. and interleukin-6 (17,367 pg/ml [4,539–22,532] vs. 2,403 pg/ml [917–3,724], p = 0.043) doi: 10.3389/fmed.2021.779038 levels. No significant differences in the pre- and post-treatment interleukin-10 levels Frontiers in Medicine | www.frontiersin.org 1 January 2022 | Volume 8 | Article 779038 Ruiz-Rodríguez et al. Hemoadsorption in COVID-19 (22.3 pg/ml [19.2–191] vs. 5.6 pg/ml [5.2–36.6], p = 0.068) were observed. Improvements in oxygenation (prehemoadsorption PaO2 /FIO2 ratio 103 [18.4] vs. posthemoadsorption PaO2 /FIO2 ratio 222 [20.9], p = 0.029) and in the organ dysfunction (prehemoadsorption SOFA score 9 [4.75] vs. posthemoadsorption SOFA score 7.7 [5.4], p = 0.046) were observed. ICU and in-hospital mortality was 33.7%. Conclusions: In this case series, critically ill patients with COVID-19 with severe acute respiratory failure refractory to prone positioning and hypercytokinemia who received adjuvant treatment with cytokine hemoadsorption showed a significant reduction in IL-6 plasma levels and other inflammatory biomarkers. Improvements in oxygenation and SOFA score were also observed. Keywords: SARS-CoV-2 pneumonia, hemoadsorption, acute respiratory distress syndrome (ARDS), hypercytokinemia, COVID-19 INTRODUCTION This study hypothesizes that cytokine hemoadsorption may improve the hyperinflammatory profile and organ dysfunction Clinicians face several challenges when taking care of patients in the selected critically ill COVID-19 patients. This study with coronavirus 2019 disease (COVID-19) (1), as the disease aimed to evaluate cytokine hemoadsorption as rescue therapy presents three distinct stages of disease progression. Each in critically ill patients with severe SARS-CoV-2 pneumonia, stage corresponds to the different clinical profiles according acute respiratory failure refractory to standard maneuvers, to individual responses to therapy and different prognoses and hypercytokinemia. (2). These three stages determine the severity of SARS-CoV- 2 pneumonia: early, pulmonary, and hyperinflammatory. The hyperinflammatory stage is characterized by a multisystemic METHODS inflammatory syndrome, in which serum levels of inflammatory Patients and Ethics Approval biomarkers increase, resulting in a high risk of organ dysfunction In this single center, observational, and retrospective study, and death (3). The “cytokine storm” plays a central role in the critically ill patients with COVID-19 who received cytokine pathophysiology of the disease (4). In the former reports from hemoadsorption using CytoSorb R (Cytosorbents Europe, Berlin, China, the cytokine storm was recognized as a clinical feature Germany) adsorbent, between March 3, 2020 and June 22, 2020 associated with the severity of the clinical condition (5). were eligible. All patients were admitted to the ICU of Vall As a consequence, the resulting inflammatory response d’Hebron University Hospital, Barcelona, Spain. The study was is not homogeneous throughout the course of the disease approved by the local Clinical Research Ethics Committee (PR (6, 7). During the asymptomatic phase, hypercytokinemia is (AG) 270/2020), and the need for informed consent was waived. not clinically evident, and, in the subsequent stages, massive cytokine release worsens the clinical course of the disease Inclusion and Exclusion Criteria (8). This progression correlates with the fact that although The inclusion criteria were the presence of acute respiratory an important cytokine elevation begins in the first 24 or 48 h failure (PaO2 /FI O2 [arterial oxygen pressure (Pa O2 ), inspired of presentation, the clinical hyperinflammatory state becomes fraction of oxygen (FI O2 )] ratio < 150) with poor response evident on days 7–10 from the onset of symptoms. At this stage, to the prone position, hyperinflammatory state, manifested as clinical deterioration is ubiquitous, and acute respiratory failure interleukin-6 (IL-6) hypercytokinemia (IL-6 > 1,000 pg/ml), and occurs progressively. In the lung, hypercytokinemia leads to increased levels of ferritin and D-dimer (DD). Poor response diffuse alveolar damage, hyaline membrane formation, thrombus to prone positioning was considered when PaO2 /FiO2 ratio formation, fibrin exudates, and fibrotic healing (9), resulting remained <150 after the prone position. The exclusion criteria in acute respiratory distress syndrome (ARDS) (10), whose were all patients who did not meet the aforementioned criteria frequency is up to 26% in SARS-CoV-2 infection (11, 12). or had a limitation of life-sustaining care, pregnant patients, or However, potentially useful adjuvant treatments do not fit patients who had other indications for cytokine hemoadsorption. all the patients. Early in the course of COVID-19, avoiding immunosuppression is recommended. In advanced stages, Analyzed Data and Scores immunomodulation is a cornerstone for treatment interventions. The plasma concentrations of inflammatory biomarkers were Thus, it is relevant to identify the subgroup of patients who analyzed, including IL-6, IL-10, DD, and C-reactive protein develop a hyperinflammatory response (13), as they could benefit (CRP) on ICU admission, immediately before hemoadsorption from specific therapies, such as immunomodulation using blood initiation (prehemoadsorption), and after the procedure purification strategies (14). Cytokine hemoadsorption therapy (posthemoadsorption). The severity of the disease was could be a promising therapeutic intervention in patients with evaluated with the Acute Physiology and Chronic Health severe acute respiratory failure (15–17). disease Classification System (APACHE) II (18) and Sequential Frontiers in Medicine | www.frontiersin.org 2 January 2022 | Volume 8 | Article 779038 Ruiz-Rodríguez et al. Hemoadsorption in COVID-19 Organ Failure Assessment (SOFA) scores (19). Both scores RESULTS were calculated using the worst parameters measured during the first 24 h of admission. Organ dysfunction was assessed Characteristics of the Study Population by calculating the SOFA score before and after the treatment Among a total of 343 patients who were admitted to the with hemoadsorption. ICU due to severe infection of SARS-CoV-2, six patients Acute respiratory distress syndrome was defined according to received treatment with CytoSorb R (Table 1). During the study the Berlin definition criteria (20). Data on the incidence of acute period, hemoadsorption was performed in another patient whose kidney injury (AKI) or failure, and the need for the continuous indication was refractory septic shock secondary to the intestinal renal replacement therapy (CRRT), were collected according perforation. This patient was excluded from this study. to the latest kidney disease: Improving Global Outcomes From a total of six patients, 5 (83.0%) were male; mean (KDIGO) Clinical Practice Guideline criteria (21). Pa O2 /FI O2 age 57.0 years (10.5). Patient characteristics, other treatments ratio was calculated before and after each hemoadsorption received, and outcomes are presented in Table 1. All the patients session. Also, the use of high doses of methylprednisolone fulfilled the Berlin criteria for severe ARDS. All patients required (∼1.5–2 mg/kg), systemic anticoagulation (22), number of days mechanical ventilation and prone positioning. The mean SOFA on mechanical ventilation, duration of ICU stay, and ICU score was 5.2 (1.5) at ICU admission, and the mean Pa O2 /Fi O2 and in-hospital mortality were collected. The study fulfilled ratio was 97.5 (14.6). The levels of DD were 559 mcg/ml (254– the “Strengthening the reporting of observational studies 2,643), CRP 19.5 mg/dl (13.4), ferritin 967 mcg/L (682–2,116) in epidemiology (STROBE)” checklist for the observational and IL-6 1,163 pg/ml (52–2,775). studies (23). The mean duration of the mechanical ventilation was 15.2 days (7.2). Three (50%) patients developed COVID-19-associated AKI and required CRRT. The mean ICU stay was 17.2 days (8.0), CytoSorb® and Continuous Renal and ICU and in-hospital mortality was 33.7%. Replacement Therapy CytoSorb R is a highly bio- and hemocompatible cytokine Hemoadsorption adsorber approved for use in conditions with increased levels Patient eligibility for the cytokine hemoadsorption was assessed of cytokines. The device is composed of porous polymer beads between days 3 and 4 of ICU admission. At inclusion, clinical within a huge and efficient surface area. It allows for adsorption parameters of the organ dysfunction and inflammation had and permanent binding of molecules in the 5–60 kDa range. worsened in all patients. The mean SOFA score was 9 (4.75), This range includes the vast majority of cytokines and other and Pa O2 /Fi O2 ratio was 103 (18.4). Levels of DD were 17,868 inflammatory molecules. mcg/ml (4,196–45,287), CPR 12.9 mg/dl (10.6), ferritin 1,539 The CytoSorb R filter was connected posthemofilter via a close mcg/L (764–27,414), IL-6 17,367 pg/ml (4,539–22,532), and IL- loop circuit to the CRRT pump (Prismaflex, Gambro Lundia 10 22.3 pg/ml (19.2–191) (Table 2). All the patients underwent AB, Lund, Sweden). CRRT was delivered using the continuous cytokine hemoadsorption (5 patients received one session of hemodiafiltration mode using an MA 150 R hemofilter (Baxter, CytoSorb R hemoadsorption [each session of variable duration], Illinois, US) at a blood flow rate of 200 ml/min. Anticoagulation and one patient received two 24-h sessions). The mean perfusion was performed with citrate or heparin. time was 16 (9) h. The circuit patency determined the duration of hemoadsorption sessions in 3 patients (circuit clotting occurred Measurement of Plasmatic Levels of at 3, 8, and 16 h). Cytokines Plasmatic levels of IL-6 were measured using the automated Inflammatory Parameters and Organ quantitative immunoassay Cobas R (Roche diagnostics Dysfunction International Ltd, Switzerland), following the instructions All inflammatory parameters, except for IL-10 levels, significantly of the manufacturer. Circulating levels of IL-10 and soluble decreased after treatment (posthemoadsorption DD levels 4,488 CD25 (IL-2Ra) were determined using the microfluidics-based mcg/ml [3,166–17,076], p = 0.046; posthemoadsorption CRP 3.5 quantitative immunoassay, ELLA R (ProteinSimple, California, mg/dl [2.8], p = 0.028; posthemoadsorption ferritin levels 1,197 US), following the instructions of the manufacturer. mcg/L [524–3,857], p = 0.046; posthemoadsorption IL-6 levels 2.403 pg/ml [917–3.724], p = 0.043; and posthemoadsorption Statistical Analysis IL-10 levels 5.6 pg/ml [5.2–36.6], p = 0.068). According to the variable distribution, descriptive data were Improvements in oxygenation (posthemoadsorption expressed as mean (SD) or median (interquartile range Pa O2 /Fi O2 ratio 222 (20.9), p = 0.029) and the organ dysfunction [IQR], 25–75%). Mann-Whitney U-test was used to compare were also observed (posthemoadsorption SOFA score 7.7 [5.4], p continuous variables and Fisher’s test for categorical variables. = 0.046) (Table 2). All the statistical tests were 2-sided, and a p-value < 0.05 was considered statistically significant. An analysis of the required DISCUSSION sample size was not performed because of the observational characteristics of the study. Data analysis was conducted using Main Findings of This Study the statistical software package PASW Statistics for Windows, This retrospective study describes the potential benefits of Version 18.0 (SPSS Inc, Chicago, Illinois, US). CytoSorb R hemoadsorption in critically ill patients with Frontiers in Medicine | www.frontiersin.org 3 January 2022 | Volume 8 | Article 779038 Ruiz-Rodríguez et al. Hemoadsorption in COVID-19 TABLE 1 | Clinical patient characteristics. Previous Experience With Cytokine Variable Result Hemoadsorption Several recommendations regarding the use of cytokine Characteristics of the study population hemoadsorption in SARS-CoV-2 pneumonia have been Male gender 5 (83.0%) published recently. The National Health Commission and Age (years) 57.0 (10.5) National Administration of Traditional Chinese Medicine APACHE II 19.5 (6.1) recommends CytoSorb R hemoadsorption to treat severe and critical cases of COVID-19 (24). The Brescia Renal Covid Body mass index 29 (3) Task Force recommends CytoSorb R hemoadsorption in the Comorbidities patients with COVID-19 admitted to ICU who have ARDS History of smoking (n, %) 2 (33.3%) or AKI-requiring CRRT (25). The Panamanian Association of Arterial Hypertension (n, %) 3 (50%) Critical Medicine and Intensive Therapy recommends using Diabetes mellitus (n, %) 2 (33.3%) CytoSorb R in patients with hyperlactatemia and high-dose Chronic Obstructive Pulmonary Disease (n, %) 0 (0%) vasopressors who do not respond to standard therapy. Patients Malignant condition or immunosuppression (n, %) 0 (0%) with severe ARDS with high-ventilatory support requirements or Chronic kidney disease (n, %) 0 (0%) candidates for the use of extracorporeal membrane oxygenation Liver disease (n, %) 0 (0%) (ECMO) therapy are also considered (26). The Colombian consensus suggests using CytoSorb R in patients with cytokine Congestive heart disease (n, %) 0 (0%) storm syndrome when there is a lack of treatment response, Coronary heart disease (n, %) 0 (0%) and while evaluating the individual prognosis of the patient Organ dysfunction and supportive treatment (27). On April 10, 2020, the United States of America Food and SOFA ICU admission 5.2 (1.5) Drug Administration issued an Emergency Use Authorization PaO2 /FI O2 ratio 97.5 (14.6) for CytoSorb R to treat patients with 18 years of age or older Prone position (n, %) 6 (100%) with confirmed COVID-19 admitted to the ICU with confirmed Sepsis (n, %) 0 (0%) or imminent respiratory failure and specifically early ARDS, Shock (n, %) 1 (16.7%) severe disease or life-threatening disease defined as respiratory AKI (n, %) 3 (50.0%) failure, septic shock or the multiorgan dysfunction (28). Despite these recommendations, clinical experience is scarce and comes CRRT (n, %) 3 (50.0%) mainly from case reports and some case series (29–31). Tocilizumab (n, %) 4 (66.7%) Corticoesteroids 2 mg/kg (n, %) 1 (16,7%) Anticoagulation (n, %) 4 (66.7%) Characteristics of the Study Population. VAP (n, %) 2/6 (33.3%) Target Patient Population Hemoadsorption The selection of patients with COVID-19 for receiving cytokine Duration hemoadsorption (h) 16.0 (9.0) hemoadsorption is critical and should be individualized. There ◦ are two clinical phenotypes of the patients with COVID-19 N sessions hemoadsorption 1.2 (1.0) (11). One phenotype is characterized by a mild or moderate Inflamatory parameters on admission disease with low-viral loads. These patients have preserved DD (n.v. < 0.5mcg/ml) 559 (254–2643) interferon responses with regulated production of cytokines and CRP (n.v. < 0.5mg/dl) 19.5 (13.4) show rapid recovery from initial lymphopenia. Thus, they are Ferritin (n.v.<336 mcg/L) 967 (682–2116) unlikely to benefit from cytokine hemoadsorption. However, IL-6 (n.v. < 4.3 pg/ml) 1163 (52–2775) selected patients in the second phenotype, characterized by Outcomes a severe disease with a high risk of death, high-viral loads, Days on mechanical ventilation 15.2 (7.0) insufficient interferon response, sustained lymphopenia, and ICU stay (days) 17.2 (8.0) a very significant elevation of cytokines, could benefit from cytokine hemoadsorption. In this study, patients were more ICU Mortality (n, %) 2 (33.3%) suitable to receive cytokine hemoadsorption if they were Inhospital Mortality (n, %) 2 (33.3%) more severely ill and developed severe acute respiratory AKI, acute kidney injury; APACHE II, Acute Physiology and Chronic Health disease failure refractory or poorly responsive to prone positioning, in Classification System II; CRRT, continuous renal replacement therapy; CRP, C-reactive association with a hyperinflammatory state (determined by very protein; DD, D-dimer; ICU, intensive care unit; SOFA, sequential organ failure assessment; high levels of biomarkers, such as IL-6, ferritin, and DD). All VAP, ventilator-associated pneumonia. patients in this study presented a considerable deleterious clinical condition, with a mean PaO2 /FI O2 ratio of 103 (18.4). refractory acute respiratory failure due to COVID-19 and There is a lack of studies evaluating cytokine hemadsorption hypercytokinemia. Hemoadsorption was associated with a in critically ill patients with COVID-19, and some of them reduction in inflammatory biomarkers, improved oxygenation, have included heterogeneous populations of critically ill patients. and multiorgan dysfunction. Rampino et al. (32) reported a case series of 9 consecutive Frontiers in Medicine | www.frontiersin.org 4 January 2022 | Volume 8 | Article 779038 Ruiz-Rodríguez et al. Hemoadsorption in COVID-19 TABLE 2 | Comparison of prehemoadsorption (pre-HA) and posthemoadsorption (post-HA) parameters. ICU admission Pre-HA Post-HA p-value SOFA 5.2 (1.5) 9 (4.75) 7.7 (5.4) p = 0.046 PaO2 /FI O2 ratio 97.5 (14.6) 103 (18.4) 222 (20.9) p = 0.029 DD (n.v. < 0.5 mcg/ml) 559 (254–2,644) 17,868 (4,196–45,287) 4,488(3,166–17,076) p = 0.046 CRP (n.v. < 0.5 mg/dl) 19.5 (13.4) 12.9 (10.6) 3.5 (2.8) p = 0.028 Ferritin (n.v. < 336 mcg/L) 967 (682–2,116) 1,539 (764–27,414) 1,197 (524–3,857) p = 0.046 IL-6 (n.v. < 4.3 pg/ml) 1,163 (52–2,775) 17,367 (4,539–22,532) 2,403 (917–3,724) p = 0.043 IL-10 (n.v. < 7.8 pg/ml) – 22.3 (19.2–191) 5.6 (5.2–36.6) p = 0.068 DD, D-dimer; Fb, fibrinogen; HA, hemoadsorption; IL-6, interleukin 6; IL-10, interleukin 10; CRP, C-reactive protein; n.v., normal values; SOFA, Sequential Organ Failure Assessment score. critically ill patients with SARS-CoV-2 and acute respiratory intubation. Damiani et al. (33) showed the median values of failure requiring continuous positive airway pressure. In this IL-6 before hemoadsorption were 355 pg/ml (IQR 263–466), study, no patients required invasive mechanical ventilation. Their 118 pg/ml (IQR 19–221, p = 0.003) at treatment end and 169 eligibility criteria were confirmed SARS-CoV-2 pneumonia and pg/ml (IQR 61–253, p = 0.03) 24 h after therapy. A significant a sum of Pa O2 /Fi O2 ratio < 200 mm Hg, CRP levels >10 decrease in CRP and an increase in Pa O2 /Fi O2 ratio were also mg/dl, and a lymphocyte count <1,500/mm3 . Damiani et al. observed. The improvement in the inflammatory profile was (33) delivered hemoadsorption with CytoSorb R for 24 to 48- associated with progressive improvements in the respiratory h sessions to 11 patients with COVID-19 requiring mechanical function. Nassiri et al. (34) reported that the Pa O2 /Fi O2 ratio, ventilation due to rapidly progressive ARDS after a median SOFA score, and inflammatory biomarkers (procalcitonin, CRP, of 3 days (range 0–4 days) from hospital admission. Nassiri and ferritin) improved significantly, and the authors reported et al. (34) used CytoSorb R in 26 patients with COVID-19- a mortality rate of 19.2%. A potential limitation of this study associated moderate ARDS (Pa O2 /Fi O2 ratio < 200) and hyper is that cytokine levels were not reported. Paisey et al. (35) inflammation (CRP > 50 mg/L and ferritin > 1,500 mcg/L). proposed hemoadsorption as an adjunctive treatment leading to Of all patients, 46.2% received mechanical ventilation. Paisey a reduction in ferritin, CRP, procalcitonin, and lactate levels. Yet, et al. (35) reported a case series of 15 patients with severe no significant differences were found in IL-6 and IL-10 pre- and COVID-19 that received cytokine hemoadsorption (five HA-330 post-treatment levels. In these patients, hypercytokinemia was cartridges and 10 CytoSorb R adsorbents). All the patients needed moderate, although they showed a hyperinflammatory profile invasive mechanical ventilation and CRRT, and 11 received based on ferritin and CPR levels. Villa et al. (36) delivered the ECMO support. In a multicenter study, Villa et al. (36) evaluated hemoadsorption therapy after a median of 3.6 days (IQR 3.7) 37 patients who had received cytokine hemoadsorption using the from ICU admission and 14 days (IQR 10.0) from the symptom oXiris R membrane. The indication for oXiris R was biochemical onset. The decrease of IL-6 concentration was significant, and clinical evidence of systemic inflammation associated with especially during the first 24 h of treatment (from baseline levels AKI, hemodynamic instability, or multiorgan dysfunction. All of 1,230 pg/ml [IQR 895] to 479 pg/ml [IQR 531] at 24 h after the patients received mechanical ventilation. treatment, 320 pg/ml [IQR 259] at 48 h, and 160 pg/ml [IQR 141] at 72 h [p = 0.001 for each time point]). The reduction in Biomarker Levels and Organ Dysfunction serum IL-6 concentration levels correlated with improved organ Throughout Hemoadsorption in Relation to function, particularly hemodynamic and pulmonary function. A Outcomes slight decrease in the observed mortality rate compared with the In general, critically ill patients with COVID-19 do not show predicted mortality rate, calculated by the APACHE IV score, was increased plasma levels of biomarkers as other populations of also observed. critically ill patients (e.g., septic shock or sepsis with patients with The results of this study are different from the recently ARDS). Previous studies have found mild-to-moderate elevations published CYCOV trial (38), in which 34 patients with of CRP, IL-6, and ferritin. (37) However, there are no well- severe COVID-19 pneumonia requiring ECMO were included. defined thresholds of biomarkers to consider the initiation of Seventeen patients were treated with cytokine hemoadsorption cytokine hemoadsorption. Given the heterogeneity of individual for 72 h. No significant differences in IL-6 levels were observed responses and the numerous underlying factors that affect levels between the two groups after 72 h of cytokine hemoadsorption. of biomarker, it is uncertain whether valid thresholds will be The median IL-6 concentrations decreased from 357 pg/ml (IQR determined shortly. 177.4–118.0) to 98.6 pg/ml (71–192.8) in the cytokine adsorption The results of this study are engaging and coincide with the group and from 289.0 pg/ml (87–787.0) to 110.0 pg/ml (48– previous studies. Rampino et al. (32) documented reductions 198.5) in the control group. In contrast, the median baseline in proinflammatory cytokines (e.g., IL-6) in patients receiving IL-6 levels were very high (17,367 pg/ml [4,539–22,532]), and cytokine hemoadsorption therapy. All patients who received the the reduction in IL-6 levels and inflammatory biomarkers was treatment survived, and only two of them needed endotracheal substantial. The results of the CYVOV trial are not comparable Frontiers in Medicine | www.frontiersin.org 5 January 2022 | Volume 8 | Article 779038 Ruiz-Rodríguez et al. Hemoadsorption in COVID-19 with the results of this study, as the rate of cytokine removal size calculation because of the observational characteristics of by hemoadsorption depends on the presence of baseline high- the study. concentration levels of cytokines in plasma (39). In this study, the strategy for delivering cytokine CONCLUSIONS hemadsorption was different from other studies that used fixed hemoadsorption regimens. Single 24-h sessions of In this case series, critically ill patients with COVID-19 hemoadsorption were planned to be delivered (only one patient with severe acute respiratory failure refractory to prone required two sessions of 24 h). Real-time IL-6 levels were positioning and hypercytokinemia who received adjuvant monitored during the hemoadsorption sessions, which allowed treatment with cytokine hemoadsorption showed a significant us to withhold the treatment at 24 h if IL-6 levels had been reduction in IL-6 plasma levels and other inflammatory reduced, and the patient had clinical improvement. As observed biomarkers. Improvements in oxygenation and SOFA score were by Damiani et al. (33) and Paisey et al. (37), no significant also observed. Cytokine hemoadsorption could be a safe and differences were found in the reduction of IL-10 levels. However, effective rescue therapy for patients with refractory COVID-19 the lack of effect over IL-10 levels may be secondary to the acute respiratory failure. slightly increased baseline levels and the small sample size. Cytokine hemoadsorption could be considered an effective and safe rescue therapy for highly selected critically ill patients DATA AVAILABILITY STATEMENT with COVID-19. Further studies and randomized controlled The original contributions presented in the study are included trials in critically ill patients with COVID-19 with refractory in the article/supplementary materials, further inquiries can be acute respiratory failure and hypercytokinemia should be directed to the corresponding author/s. conducted to accurately narrow the indications and clinical benefits of the cytokine hemoadsorption. Limitations ETHICS STATEMENT This study has some limitations. First, this is a single- center study including a small number of patients with The study was approved by the Local Clinical Research no control group. Thus, the findings of this study should Ethics Committee (PR (AG) 270/2020), and the need for be confirmed in larger comparative studies and cannot be informed consent was waived. The patients/participants extrapolated to other ICU settings; moreover, the complexity provided their written informed consent to participate in of the conferred difficulty of the patients in determining this study. the effect of CytoSorb R alone on patient outcomes. Second, the patient inclusion process was not consecutive. Given the AUTHOR CONTRIBUTIONS unprecedented pandemic situation, it was impossible to ensure that all patients meeting the inclusion criteria were evaluated All authors involved in providing care for the patient and writing for eligibility. Third, we have not performed the sample and reviewing the manuscript. REFERENCES 7. 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Managing patients in dialysis and with kidney transplant infected with Covid- Conflict of Interest: The authors declare that the research was conducted in the 19. G Ital Nefrol. (2020) 37:2020-vol2. absence of any commercial or financial relationships that could be construed as a 26. Asociación Panameña de Medicina Critica y Terapia Intensiva. GUÍAS potential conflict of interest. NACIONALES DE ATENCIÓN DE PACIENTES ADULTOS COVID-19 VERSION 2.0. Published on March 22nd on https://medcriticapanama.com Publisher’s Note: All claims expressed in this article are solely those of the authors 27. González C, Yama E, Yomayusa N, Vargas J, Rico J, Ariza A et al. and do not necessarily represent those of their affiliated organizations, or those of Consenso colombiano de expertos sobre recomendaciones informadas en the publisher, the editors and the reviewers. Any product that may be evaluated in la evidencia para la prevención, el diagnóstico y el manejo de la lesión this article, or claim that may be made by its manufacturer, is not guaranteed or renal aguda por SARS-CoV-2/COVID-19. Rev Colomb Nefrol. (2020) 7:89– 117. doi: 10.22265/acnef.7.Supl.2.473 endorsed by the publisher. 28. U.S. Food and Drug Administration. CytoSorb R 300 mL Device Approved by FDA for Emergency Treatment of COVID-19. Silver Spring, MD: FDA (2020). Copyright © 2022 Ruiz-Rodríguez, Chiscano-Camón, Ruiz-Sanmartin, Palmada, 29. Rizvi S, Danic M, Silver M, LaBond V. Cytosorb filter: an adjunct for survival Paola Plata-Menchaca, Franco-Jarava, Pérez-Carrasco, Hernández-González and in the COVID-19 patient in cytokine storm? A case report. Heart Lung. (2021) Ferrer. This is an open-access article distributed under the terms of the Creative 50:44–50. doi: 10.1016/j.hrtlng.2020.09.007 Commons Attribution License (CC BY). The use, distribution or reproduction in 30. Mezger M, Eitel I, Ensminger S, Pogorzalek D, Huang Z, Graf T. Sequential use other forums is permitted, provided the original author(s) and the copyright owner(s) of hemoadsorption using cytosorb and biosky filter-technology in A COVID- are credited and that the original publication in this journal is cited, in accordance 19 patient suffering from severe ARDS. Arch Clin Med Case Rep. (2020) with accepted academic practice. No use, distribution or reproduction is permitted 4:969–77. doi: 10.26502/acmcr.96550286 which does not comply with these terms. Frontiers in Medicine | www.frontiersin.org 7 January 2022 | Volume 8 | Article 779038