Effect of extracorporeal hemoadsorption in critically ill patients with COVID-19: A narrative review

Abstract

COVID-19 has been affecting the world unprecedentedly and will remain widely prevalent due to its elusive pathophysiological mechanism and the continuous emergence of new variants. Critically ill patients with COVID-19 are commonly associated with cytokine storm, multiple organ dysfunction, and high mortality. To date, growing evidence has shown that extracorporeal hemoadsorption can exert its adjuvant effect to standard of care by regulating immune homeostasis, reducing viremia, and decreasing endotoxin activity in critically ill COVID-19 cases. However, the selection of various hemofilters, timing of initiation and termination of hemoadsorption therapy, anticoagulation management of extracorporeal circuits, identification of target subgroups, and ultimate survival benefit remain controversial. The purpose of this narrative review is to comprehensively summarize the rationale for the use of hemoadsorption in critically ill patients with COVID-19 and to gather the latest clinical evidence in this field.

1 Introduction

The current pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with a spectrum of disease severity ranging from mild symptoms to critical illness. A recent systematic analysis found that the number of people who died from COVID-19 from Jan 1, 2020, to Dec 31, 2021 globally reached 18.2 million (1), which was much higher than the WHO official statistics (2).

The pathophysiological changes in the course of COVID-19 can be prevented and treated through various approaches. Efforts to develop effective means of prevention and treatment mainly target the host immune response to COVID-19 (3). For example, as the key to limiting SARS-CoV-2 transmission, real-world data have shown that vaccination has considerable effectiveness against severe disease and hospitalization despite the slow vaccination rate in some regions (4, 5). Antiviral medications such as remdesivir, and anti-inflammatory regimens such as corticosteroids, interleukin-6 (IL-6) inhibitors, and Janus kinase inhibitors have also been reported to improve clinical outcomes in hospitalized COVID-19 patients in specific subgroups (6–9). The emergence of new multiple variant infections indicates that protection against severe disease is really anticipated (10). Additionally, the reduction in the infection-fatality ratio in the postvaccination era should be further evaluated (11). Post-COVID syndrome, which is closely related to host immune dysfunction, has also attracted much attention recently (12).

Along with the characteristics and disease course of critically ill COVID-19 patients continuously evolving throughout the pandemic (13), we should note that treatment strategies still remain limited in a subgroup of critically ill COVID-19 patients with cytokine storm and multiple organ dysfunction syndrome (MODS), such as acute kidney injury (AKI) and acute respiratory distress syndrome (ARDS) (3). The truth is that the effectiveness of several explored therapeutic approaches, including antiplatelet agents and high-dose convalescent plasma, on the survival of critically ill COVID-19 patients is not promising (14–16). The conflicting study outcomes of anti-interleukin drugs also remind us that broader immunoregulation in severe patients is still required to prevent malignant disease progression (17).

Extracorporeal hemoadsorption, an important adjuvant treatment to standard of care, has been used in various critical care settings during the past two decades (18). Accumulating evidence collectively shows that the selective or nonselective removal of multiple inflammatory mediators and circulating toxins from the bloodstream during hemoadsorption sessions has an immediate effect on the regulation of host inflammatory response, but the evidence for beneficial effects is uncertain (19). More recently, new indications are developing in this field, and novel hemofilters are available for clinical use (20). An early systematic review recommended against the indiscriminate use of extracorporeal hemoadsorption in critically ill COVID-19 patients outside of investigational clinical trials. However, this analysis only included low-quality case series and observational studies with no randomized studies included (21). In contrast, another narrative review that included 16 studies (including a controlled trial) demonstrated that hemoadsorption therapy is an alternative salvage treatment method in critically ill COVID-19 patients, but it also has methodological shortcomings in data analysis and thus still needs to be supported by stronger evidence (22). Meanwhile, previously published narrative reviews were mostly based on previous practical experience with other diseases such as sepsis, severe acute respiratory syndrome and middle east respiratory syndrome (MERS) instead of COVID-19 (23, 24).

Herein, we summarize the rationale and the latest evidence for hemoadsorption that are exclusively applied in the specific context of COVID-19 until January 20, 2023. We also discuss perspectives for future research design and clinical application of hemoadsorption-based techniques in critically ill COVID-19 patients.

2 Rationale for the use of hemoadsorption in severe COVID-19 patients

SARS-CoV-2 is a highly pathogenic virus. As shown in Figure 1, when SARS-CoV-2 invades the body, the first responder is innate immunity, like monocytes, macrophages, neutrophils, dendritic cells, natural killer cells, and then adaptive immunity, like T helper 1 (Th1), Th2 cells and B cells (25). Innate immune responses induced by pattern recognition receptors (PRRs) signaling activate effector cells to mediate viral clearance (26). Interferons (IFNs), classified as interferon I (IFN I), IFN II (IFN-γ) and IFN III, are critical in the initiation of the innate immune response, while delayed IFN I secretion induced by SARS-CoV-2 will reduce chemotaxis, leading to a weakened innate immune response (27). Typically, the adaptive immune response in COVID-19 patients shifts to the Th2 phenotype, and Th2 cells exerts anti-inflammatory effects by secreting cytokines such as IL-4, IL-5 and IL-10, which contributes to the control of SARS-CoV-2 infection rapidly (28). While the weakened innate immune response will in turn lead to enhanced viral replication and hyperactivation of Th1 cells, which subsequently activates macrophages by releasing IFN-γ, thus causing the production and secretion of IL-1, IL-6, IL-8 and transforming growth factor (TGF-β), the latter of which activate Th17 cells to secrete IL-17, and together generate a cytokine storm, which is characterized by an aberrant, rapid, excessive and prolonged inflammatory response to cytokines/chemokines (29). The cytokine storm originates in the lung, and then pro-inflammatory cytokines and chemokines are released from the tissue and circulated to other parts of the body (30). To date, it has been widely accepted that abnormal immune response to SARS-CoV-2 infection is mainly characterized by hyperinflammation, hypercoagulation, and endothelial dysfunction, which are all inter-related with cytokine storm, leading to MODS, such as ARDS and AKI, and subsequent morbidity and mortality (31, 32). Meanwhile, a few patients with critically ill COVID-19 may have mild symptoms in the early stages but suddenly deteriorate or even die in the later stages, further making cytokine storm in the spotlight. Additionally, hemophagocytic lymphohistiocytosis and multisystem inflammatory syndrome associated with SARS-CoV-2 have been recognized as complications due to cytokine storm (33–35). In this regard, controlling the inflammatory response may be as important as targeting the virus in critically ill COVID-19 patients (36). However, the limited understanding of specific inflammatory responses in different pathologies and complex networks of inflammatory responses are insufficient to control the overall inflammatory response. For instance, sepsis-like syndromes may also occur due to viral per se or superimposed bacterial infections (37). Unfortunately, microorganisms cannot be identified in up to one-third of the cultures, which will hinder the timely initiation of appropriate antibiotic therapy (38). Meanwhile, irrationally direct use of nonspecific immunomodulators such as corticosteroids can add insult to injury in critically ill COVID-19 patients (39).

Figure 1

Current evidence suggests that conventional blood purification modalities such as dialysis, hemofiltration and plasmapheresis show insufficient performances in removing middle to large cytokine molecules and pathogens (40). Therefore, the rationale for the use of hemoadsorption is indeed strong when specific inflammatory mediators (e.g., cytokines and endotoxin) in critically ill COVID-19 patients with cytokine storm and MODS are selectively targeted, as their reduced levels are associated with decreased morbidity and mortality (18). Because of a lack of well-defined biomarker thresholds to consider the initiation of hemoadsorption, the rate of cytokines removal by hemoadsorption is thought to depend on the high-level of baseline cytokine concentrations in plasma (41), implying that the presence of higher levels of cytokines is associated with a better benefit from cytokine hemoadsorption. Along with a number of novel hemofilters being created in quick succession, hemoadsorption therapy with immunomodulation and toxin clearance is a promising alternative to standard of care in critically ill COVID-19 patients. Considering the interactions of adsorptive hemofilters with pathological mechanisms caused by COVID-19, the potential mechanisms of the effect of hemoadsorption in severe COVID-19 are as follows: 1) reversing the state of immune dysregulation through the elimination of peak cytokine concentrations (42–44); 2) interrupting cascade immune reactions by modulating the composition and kinetic redistribution of mediators in body fluids (45, 46); 3) restoring immune function by regulating monocytes, neutrophils and lymphocytes to increase their sensitivity to drugs and to reduce virus reactivation (47–49); 4) directly eliminating SARS-CoV-2 viral load and pathogen-associated molecular patterns (endotoxins, etc.) (50). Basic characteristics of currently available hemoadsorption therapy in COVID-19 patients are shown in Table 1.

3 Current evidence for hemoadsorption use in severe COVID-19 patients

3.1 oXiris membrane

The oXiris membrane (Baxter International, Deerfield, IL, USA) employs a unique polyethyleneimine coating to modify the conventional AN69 membrane, with significant endotoxin and cytokine adsorption properties by the polyethyleneimine layer and the bulk negatively charged hydrogel structures, respectively (51, 65). In addition, the oXiris membrane exhibits antithrombogenic properties due to a pre-grafted heparin layer and has long been used in continuous renal replacement therapy (CRRT) for critically ill patients with sepsis (51, 66). As severe COVID-19 patients frequently develop life-threatening AKI and cytokine storm, the oXiris membrane has been authorized for emergency use in adults with confirmed COVID-19 by the FDA since April 2020 (67).

Most small-size case series (68–71) collectively found that CRRT with the oXiris membrane significantly decreased levels of proinflammatory cytokines and improved hemodynamics and organ function in critically ill COVID-19 patients. A prospective cohort study established the fluctuation of biomarkers over time through the collection of 3,000+ accumulated hours of CRRT with the oXiris hemofilter run-time and real-time data for 44 patients, demonstrating the safety and efficacy of oXiris-CRRT in the reduction of C-reactive protein (CRP) and IL-6 levels, thereby mitigating the systemic damage caused by abnormal immune activation and stabilizing the clinical conditions of participants (46). Compared to the mortality rates calculated by the Acute Physiology and Chronic Health Evaluation (APACHE) IV score, the mean observed mortality rates were also lower after oXiris treatment (69, 71). Premužić et al. further demonstrated that critically ill COVID-19 patients with oXiris treatment survived significantly longer than other intensive care unit (ICU) COVID-19 patients (69). In contrast, a small-size single-center study reported negative results for alleviating cytokine storm in non-AKI patients with severe COVID-19, which might be attributed to the selected non-AKI with normal renal clearance patients and the relatively lower IL-6 concentration (tens of pg/mL) in COVID-19 patients than that in patients with septic shock (72). Furthermore, the differences in inflammatory sub-phenotypes, SARS-CoV-2 viral load, innate and acquired immune defense, and comorbidities may also have a certain impact on the production and release of circulating cytokines and chemokines (72). These findings suggested that routine clinical use of the oXiris membrane in non-AKI COVID-19 patients should be considered with caution.

Although current evidence collectively suggests that the use of the oXiris membrane in COVID-19 patients is well tolerated in most cases, adequate anticoagulation to maintain the patency of the extracorporeal circuit remains a challenge in COVID-19 patients with a hypercoagulable state. Compared to non-COVID-19 patients, a significantly higher incidence of metabolic alkalosis and hypercalcemia consistent with reduced filter patency was observed in COVID-19 patients undergoing CRRT with regional citrate anticoagulation (73). However, the mean half-life of the CRRT hemofilter in COVID-19 patients was similar to that in non-COVID-19 patients with septic shock because hospitalized COVID-19 patients routinely received systemic heparin for thromboprophylaxis (74). These results suggested that close monitoring of the acid-base balance appears warranted when delivering CRRT with regional citrate anticoagulation in severe COVID-19 patients.

Currently, there is an ongoing open-label randomized controlled trial (RCT) (oXAKI-COV study) comparing CRRT with the oXiris membrane vs. standard AN69 membrane during a 72-h treatment period in critically ill COVID-19 patients with AKI (NCT04597034) (75). The primary outcome of the oXAKI-COV study is the change in norepinephrine requirement by at least 0.1 mg/kg/min to maintain similar mean arterial pressure after initiation of CRRT. Secondary outcome measures included the change in interleukin serum levels (IL-6, IL-10, and TNF-α) and length of (intensive care unit) ICU stay in these patients. It is believed that the final analysis of such a high-quality RCT could provide solid evidence in this field and advance clinical practice.

3.2 Cytosorb^® adsorber

The Cytosorb^® (CytoSorbents, Monmouth Junction, NJ, USA) has long been approved for the removal of cytokines, bilirubin, and myoglobin by hemoadsorption (53, 76). The adsorber consists of a cylindrical cartridge filled with tiny, highly porous, hemocompatible polyvinylpyrrolidone-coated polystyrene-divinyl-benzene copolymer beads with a total surface area of > 40,000 m², which significantly adsorbs hydrophobic cytokine molecules within the 5–55 kDa molecular weight range (54, 77). Currently, the Cytosorb^® adsorber can be used for hemoadsorption or in series with CRRT and extracorporeal membrane oxygenation (ECMO) circuits (43, 78, 79), and the duration of Cytosorb therapy usually permits at least 72 continuous hours with device exchange every 24 hours (78). Currently, the Cytosorb^® adsorber has been broadly used in patients with critical illnesses such as infective endocarditis (80, 81), severe acute pancreatitis (82), postcardiac arrest syndrome (83), and septic shock (84) during the last decade. Early in the COVID-19 pandemic, extracorporeal hemoadsorption with the Cytosorb^® adsorber was also approved as an adjunctive therapy to remove excessive inflammatory mediators in COVID-19 patients by the European Union and FDA.

Data on clinical effectiveness are inconsistent. Most small-size observational studies or case series consistently found that CytoSorb treatment was effective in alleviating inflammation [IL-6, procalcitonin, CRP, ferritin] (85–89), decreasing D-dimer (86), and improving oxygenation and hemodynamics (88–90) in critically ill COVID-19 patients with refractory ARDS or MODS. In a case series study enrolling 6 COVID-19 patients who were characterized by severe acute respiratory failure with poor response to the prone position (PaO₂/FiO₂ [arterial oxygen pressure (PaO₂), inspired fraction of oxygen (FiO₂)] ratio remained <150 after the prone position) and hyperinflammatory state (IL-6 > 1,000 pg/ml and increased levels of ferritin and D-dimer), cytokine hemoadsorption with the CytoSorb adsorber was used as an effective and safe rescue therapy. After the CytoSorb treatment, the extra high median baseline IL-6 concentration (17,367 pg/ml [4,539–22,532]) had a significant reduction to 2.403 pg/ml [917–3.724], p = 0.043. Oxygenation also improved significantly from 103 (18.4) mm Hg to 222 (20.9) mm Hg, p = 0.029 (86). A multicenter, retrospective registry enrolling 52 patients who received veno-venous ECMO plus CytoSorb therapy at 5 medical centers in the USA also demonstrated that CytoSorb therapy was associated with lower 90-day in-hospital mortality (26.9%) than the ELSO ECMO COVID-19 Registry (52%), suggesting the potential survival benefit of cytokine adsorption (78). Moreover, CytoSorb therapy was well tolerated without any device-related adverse events reported (78, 79).

Disappointingly, data from three RCTs investigating the effect of CytoSorb^® in COVID-19 patients showed inconsistent findings (43, 79, 91). In the CYCOV study, Supady et al. found a significantly higher mortality in 14 of 17 COVID-19 patients (82%) receiving ECMO and CytoSorb therapy compared with 4 of 17 ECMO patients (24%) treated without cytokine adsorption (43). There was also no significant difference for IL-6 between the two groups after 72 h of ECMO, which might be attributed to low median baseline IL-6 levels (357 ng/L) in the intervention group. In contrast, the data from the international CytoSorb registry suggests that serum IL-6 concentrations can be reduced from a median of 5000 pg/mL down to 289 pg/mL after 24 h of cytokine adsorption in severe patients, suggesting that COVID-19 patients with higher levels of cytokines might benefit more from cytokine hemoadsorption with the Cytosorb treatment (41, 92). In another prospective, randomized controlled pilot study, 23 COVID-19 patients with vasoplegic shock and MODS were randomized to receive Cytosorb^® therapy incorporated in the continuous veno-venous hemodiafiltration (CVVHD) circuit, and 26 patients received standard CVVHD therapy (79). The results showed that hemoadsorption with Cytosorb^® did not decrease the time until resolution of vasoplegic shock (5 d, interquartile range: 4-5 d) compared with the control group (4 d, interquartile range: 3-5 d). Importantly, the ICU mortality rate was 78% in the CytoSorb^® group and 73% in the control group (unadjusted hazard ratio, 1.17 [95% CI, 0.61-2.23]; p=0.64). Meanwhile, the effects on the kinetics of inflammatory parameters (e.g., IL-6 and CRP) and catecholamine requirements were similar between the groups. The negative results may be attributed to the late intervention given the severity of disease, and the results of the statistical analysis were limited by the total number of cases. In addition, it was unclear to what extent vasoparalytic shock can be attributed to COVID-19-driven hyperinflammation or sepsis due to secondary recurrent infections, so there might be potential confounding factors. In the latest prospective, randomized controlled pilot study to date, 24 COVID-19 patients with refractory shock, hypercytokinemia (defined as IL-6 ≥500 ng/L), and indication for RRT or ECMO were enrolled. Compared with standard of care, hemoadsorption with the CytoSorb^® adsorber for up to 5 days was not associated with an significant improvement in shock resolution (33% vs. 17%, p=0.640) and survival (42% vs. 33%, p=1.0), possibly because critically ill patients with high sequential organ failure assessment (SOFA) and simplified acute physiology score II scores in this cohort were more likely to have a high in-hospital mortality (91). Altogether, the inconsistent results from RCTs call for a very careful application of Cytosorb^® in severe COVID-19 patients requiring ECMO or RRT. The indication and optimal initiation timing for CytoSorb treatment should also be investigated in future high-quality RCTs.

3.3 Seraph 100 Microbind affinity filter

A Seraph 100 Microbind affinity blood filter (ExThera Medical, Martinez, CA, USA) is an extracorporeal heparin-immobilized sorbent hemofilter that can remove pathogens from the bloodstream. On April 17th, 2020, the FDA granted COVID-19 emergency use authorizations for the Seraph 100 filter because it can utilize the structural similarity between heparin and pathogen receptors (e.g., heparan sulphate) to bind certain pathogens (55, 93). Heparin binding of the spike protein is of more clinical significance in SARS-CoV-2 than in other coronaviruses because viral RNAemia is more frequent (up to 78%) in critically ill COVID-19 patients (94, 95) and is associated with COVID-19 severity. In a small-size case series, Seraph 100 was found to decrease SARS-CoV-2 nucleocapsid protein and RNAemia/viraemia in the blood of critically ill COVID-19 patients (56).

Several cases reported that treatment with Seraph 100 was associated with a rapid improvement in oxygenation (96) and reduced D-dimers (97), and most cases behaved well tolerated and had a good clinical response (98, 99). The latest interim analysis of the COSA registry enrolling 78 COVID-19 patients showed that the observed 30-day mortality rate in the registry was lower than the mortality predicted by the coronavirus clinical characterization consortium score (11.1% vs. 38.0%) in non-ICU patients and the sequential organ failure assessment score (50.7% vs. 56.7%) in ICU patients (100). Although more than half of the treatments were performed in conjunction with renal replacement therapy, the premature end of treatment due to circuit failure was reported in 9 (8.8%) of the 102 treatments with Seraph 100, which was less likely to occur than CRRT sessions in COVID-19 patients (101). Moreover, multivariate Cox regression revealed that delayed Seraph^® 100 treatment after ICU admission (>60 h) was associated with increased mortality (100). Most recently, the PURIFY-OBS-1 study included 53 COVID-19 patients treated with Seraph 100 and another 53 matched control patients in 9 participating ICUs across the USA. The Seraph 100 group had lower Charlson comorbidity index scores and APACHE II scores with higher vasopressor-free days than the control group. On univariate analysis, Seraph 100 treatment was associated with decreased mortality with an odds ratio of 0.26 (95% CI: 0.12–0.59). However, a survival benefit with Seraph 100 treatment compared with the external Penn Medicine cohort was not observed in a post hoc analysis (102).

Currently, an RCT (NCT04547257) evaluating the safety and effectiveness of Seraph 100 in COVID-19 patients with organ dysfunction is ongoing in Germany and Spain, which takes the change in organ failure from baseline to 48 hours as a primary outcome (103). All-cause 28-day mortality, organ dysfunction-free days, and reduction of viral load will be used as secondary outcome measures. This study is estimated to be completed by the end of 2022.

3.4 Polymyxin B hemoperfusion

The Polymyxin B hemoperfusion column (Toraymyxin^®, Toray Medical, Tokyo, Japan) is composed of polymyxin B-immobilized polypropylene-polystyrene fiber fabrics. Polymyxin B hemoperfusion (PMX) is characterized by removing endotoxin for the treatment of sepsis caused by gram-negative bacteria (18). Recently, common multidrug-resistant bacterial infection in COVID-19 patients has brought it back into our sight (104), and PMX has been suggested to alleviate the peak of endotoxins in COVID-19 patients with secondary bacterial infection, thereby restoring immune homeostasis without prolonging the immunosuppressed state (105, 106). The latest approval of Canada on the use of Toraymyxin^® in severe COVID-19 was announced on April 20, 2020 (107). Besides removal of endotoxins, other possible mechanisms for Toraymyxin^® use in COVID-19 including cytokine regulation, removal of activated neutrophils, and prevention of the migration of activated leukocytes to the lungs deserve further exploration (57, 58). As the only direct hemoperfusion device targeting endotoxin, PMX can be intermittently performed without dialysis (108).

Early case reports showed an improvement in PaO₂/FiO₂ (109, 110) and a reduction in serum CRP levels after Toraymyxin^® treatment (111). Likewise, Mayuko et al. reported that Toraymyxin^® treatment decreased inflammatory markers and improved oxygenation in a COVID-19 patient with respiratory failure and hyperinflammation, which halted the patient’s progression to ARDS and avoided the need for mechanical ventilation (112). In another case series, Daisuke et al. performed 22 PMX sessions on 12 COVID-19 patients with a PaO₂/FiO₂ < 300 (113). On day 14 after the first Toraymyxin^® treatment, disease severity decreased in 7 of 12 patients, with an increased PaO₂/FiO₂ ratio and decreased urine β2-microglobulin. In addition, cytokine measurements before and after Toraymyxin^® treatment revealed decreased IL-6 levels. However, coagulation-related events still occurred in 12 of the 22 cases (54.5%) during the course of treatment, causing the need for reconfiguration of the circuit. It is still difficult to determine whether longer (>12 hours) treatment with PMX is effective in improving oxygenation (113). In a recent case series study from EUPHAS2 registry, PMX treatment was also used in 12 COVID-19 patients with sepsis. The results showed that SOFA score progressively improved after 120 hours of PMX treatment, along with a significant decrease of median endotoxin activity assay (EAA) from 0.78 [0.70-0.92] to 0.60 [0.44-0.72], suggesting that the measurement of contemporary EAA levels can be used for therapeutical efficacy monitoring during treatment (114).

3.5 HA resin hemoperfusion cartridges

HA resin hemoperfusion cartridges (HA130, HA230, HA330 and HA380) (Jafron Biomedical Co., China) have been widely used to remove a wide spectrum of endogenous and exogenous toxins (59). The cartridges contain highly biocompatible neutro-macroporous resin adsorbing beads made of styrene-divinylbenzene copolymer and have a high surface area (115). In acute inflammatory conditions such as sepsis, acute lung injury, hepatitis, and pancreatitis, HA 330 and HA 380 cartridges significantly remove excessive proinflammatory cytokines (IL-6, IL-10, TNF-α) in the bloodstream (59, 116). The recommended treatment duration of HA330 and HA380 cartridges is usually 2 to 2.5 h.

A prospective cohort study in Thailand compared the efficacy of additional hemoperfusion with standard of care on 29 severe COVID-19 patients admitted to the ICU (117). Patients who received at least 3 sessions of HA 330 hemoperfusion therapy were defined as the hemoperfusion group, while those who were treated by standard of care alone or received less than 3 sessions of HA-330 hemoperfusion were classified as the control group. Compared to the control group, patients in the hemoperfusion group showed a clinical improvement associated with a decreased SOFA score, and the addition of at least 3 sessions of HA330 hemoperfusion to standard treatment could alleviate organ failure and reduce mortality (117). However, only serum CRP levels in the patients were monitored to evaluate the effect of HA330 hemoperfusion on cytokine removal. Another single-center, matched control retrospective study enrolled 128 COVID-19 patients to investigate the efficacy of hemoperfusion in combination with standard therapy in critically ill COVID-19 patients (118). Of 55 patients in the hemoperfusion group, the number of patients who received one, two, and three or four courses of hemoperfusion was 18 (32.7%), 14 (25.4%), and 23 (41.9%), respectively. The results showed that the mortality rate was significantly lower in the HA 330 hemoperfusion group than in the matched group (67.3% vs. 89%, p= 0.002). In addition, the median length of ICU stay, duration of incubation, and median final SPO₂ were significantly higher in the hemoperfusion group than in the matched group. Likewise, Ruslan et al. demonstrated that cytokine adsorption with HA330 or Mediasorb cartridges significantly decreased CRP and fibrinogen at postfiltration in COVID-19 patients admitted to the ICU (119). However, there was no improvement in patient-centered outcomes such as SOFA scores, vasopressor use and in-hospital mortality.

Extracorporeal hemoperfusion therapies with HA resin cartridges are also associated with a number of complications, such as hematomas at insertion sites, pneumothorax, infections, and nonselective removal of nutrients and drugs (120, 121). Consequently, it is crucial to consider drug elimination during HA resin cartridge hemoadsorption sessions. The optimal timing for hemoadsorption administration in critically ill patients with COVID-19 should also be further determined in the future.

3.6 Artificial liver blood purification system

The Artificial-Liver Blood-Purification System (ALS) integrates plasma exchange, hemoperfusion, continuous hemofiltration, hemodialysis and bilirubin adsorption (61). It has been well established that ALS is effective in eliminating inflammatory mediators and small-medium molecules to maintain water/electrolyte balance and homeostasis (122). Despite the lack of solid evidence, the use of ALS in severe COVID-19 patients with cytokine storm was recommended by a Chinese expert consensus in early 2020 (122). Subsequently, through a paired study analyzing serum cytokine levels pre- and post-ALS, a nonrandomized clinical trial found that three consecutive courses of ALS treatment significantly decreased the plasma levels of 32 cytokines, including IL-6 and TNF-α (44). Furthermore, the APACHE II and SOFA scores also decreased after three consecutive sessions with ALS (44). Another case series consistently showed that the levels of IL-6 and IL-10 significantly declined after treatment with ALS (123). More recently, a multicenter, prospective study enrolling 101 participants found that, beyond a remarkable reduction in plasma IL-6 concentration, the 28-day mortality of COVID patients in the ALS group (16%) was significantly lower than that of the control group (50.98%), suggesting that ALS treatment could block cytokine storm and reduce short-term mortality (61). However, given the complexity of the modules of ALS, more detailed studies on the mechanism and long-term follow-up are needed.

3.7 Selective cytopheretic device

The selective cytopheretic device (SCD) is an immunomodulatory extracorporeal device that can promote a lower proinflammatory phenotype in circulating neutrophils and monocytes, thereby modulating the immune response and moderating tissue damage (63, 124). The device is usually placed postfilter in the CRRT circuit with regional citrate anticoagulation to facilitate leukocyte binding to the filter (125). An early case report showed that treatment with SCD in two COVID-19 patients with severe ARDS resulted in significant reductions in inflammatory markers, including procalcitonin, D-dimer, LDH, ferritin, CRP, and IL-6 (63). The PaO₂/FiO₂ ratios of the two enrolled patients also increased from 55 and 58 to 200 and 192, respectively, within hours of SCD initiation. Another recent prospective, single-arm treatment clinical trial at two academic medical centers enrolled 22 COVID-10 patients with ARDS to further evaluate the safety and clinical outcomes of extracorporeal immunomodulation treatment with SCD (49). The results of flow cytometry demonstrated that SCD selectively eliminated highly activated circulating leukocytes and diminished the inflammatory phenotype of circulating effector cells, with significant reductions in plasma levels of proinflammatory cytokines, including IL-6, IL-15, and soluble ST2 (49). More importantly, the mortality rate of the patients who received greater than 96 hours of SCD treatment was significantly lower than that of a contemporaneous control (31% vs. 81%, p < 0.012) (49). These encouraging findings suggested that early intervention with SCD in critically ill COVID-19 patients might be associated with an improvement in systemic inflammation and a potential survival benefit. It is also noteworthy that no device-related serious adverse events were observed during extracorporeal SCD sessions. A summary of prospective studies evaluating hemoadsorption in COVID-19 patients are also shown in Table 2.

4 Summary and future perspectives

Although the management of critically ill COVID-19 patients is still challenging, hemoadsorption therapy may be life-saving by regulating immune homeostasis, alleviating viraemia, and reducing endotoxin activity in critically ill COVID-19 patients. Inspiringly, data from low-quality case series and observational studies show that hemoadsorption therapy effectively reduces the levels of inflammatory mediators and improves hemodynamics and organ function. However, it is worth noting that there are still several open problems to tackle: 1) knowledge of unintended removal during hemoadsorption is still scant, and the determination of an individualized anticoagulation regime remains a puzzle that is much more complicated due to the hypercoagulable state in COVID-19 patients; 2) the optimal timing of initiation and duration of hemoadsorption and hemofilter replacement intervals are unknown; 3) the identification of specific patient subgroup who will benefit from hemoadsorption therapy is urgently required; 4) the effect of hemoadsorption therapy in patient-centered outcomes remains to be investigated. Therefore, for the moment these techniques should be considered experimental, high-quality of clinical studies with standardized study design and implementation, rigorous quality control, individualized consideration of risks and benefits, and even evidence-based advice on health economics in such resource-constrained settings are still needed.

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