key: cord-0775911-zhczgehg
authors: Lezhnina, Arina; Lem, Violetta; Blatt, Nataliya
title: Application of Extracorporeal Apheresis in Treatment of COVID-19: a Rapid Review
date: 2022-05-12
journal: Bionanoscience
DOI: 10.1007/s12668-022-00987-x
sha: 029f7ea282e45e575f7a7be74d0fbaf1e4ca5868
doc_id: 775911
cord_uid: zhczgehg

Spread of a novel coronavirus infection in 2019 caused by SARS-CoV-2 virus has become a real threat to public health all around the world. The new pandemic required the mobilization of all resources for effective treatment of COVID-19 patients. Extracorporeal apheresis methods were suggested as an addition to the therapy of severe COVID-19 patients, especially when there is a threat of cytokine storm. Cytokine storm has a complex and not fully understood mechanism, and it can result in the multiple organ failure syndrome, associated with high mortality. The main cytokines that play the key role in the cytokine storm are IL-6, IL-10, and TNF-alpha. Removal of the target pro-inflammatory cytokines from the bloodstream can be beneficial in reducing the risk of complications as well as the mortality rate. We describe and compare different methods of extracorporeal apheresis: hemoadsorption, selective plasma filtration, and plasma exchange therapy in the context of their potential use in COVID-19 treatment.

New coronavirus infection is currently the most frequent etiological cause of hospital patient mortality. According to The World Health Organization (WHO), 195 million coronavirus infection incidents were detected from 2020 to 2022 including almost 2 million of hospital patient mortality rate [1] . The main danger of coronavirus infection is the respiratory distress syndrome and multiple organ failure (MOF) [2, 3] caused by a cytokine storm [4] . Cytokine storm -is the state of uncontrollable system hyperinflammation developed in response to the excess secretion of cytokines [5] . It is noteworthy that death from coronavirus infection occurs in the first 14 days from the first symptoms manifestation, the current mortality rate is estimated from 1.36 to 5% of total patients [6, 7] .

There is currently no single effective strategy of treatment COVID-19 patients, with vaccination being an important method of infection control. However, to date 10% of population have not been vaccinated in 23 countries, 73 countries have not achieved 40% of vaccinated population, and many other countries have a prognosis to be unable to achieve the target 70% by the middle of 2022 [1] . Slow vaccination rate as well the ongoing infection spread call for development new and effective methods of treating COVID-19 patients.

The necessity of extracorporeal apheresis use, directed at the inflammatory mediator elimination and different systems of organs support, arises based on the pathophysiological failures shown in coronavirus infection patients. Extracorporeal therapy can help to prevent a multiple organ failure and increase the survival rate. Therefore, exploring the possibilities of various therapeutic apheresis methods of treating severe COVID-19 patient is still of a great importance.

Novel coronavirus infection (NKI) caused by SARS-CoV-2 virus was first reported in Wuhan (China) and widely spread all over the world [8] . The disease caused by the new coronavirus was officially named COVID-19 («Coronavirus disease 2019») [9] . On 11th of March 2021, WHO declared COVID-19 a pandemic [10] .

The main sites of entry of SARS-CoV-2 are the upper airways epithelium and gastric and intestinal epitheliocytes. SARS-CoV-2 enters the target cells through the ACE2 receptor binding. However, because SARS-CoV-2 is able to affect different organs and tissues, there are likely other receptors and coreceptors, like CD147, involved in virus entrance [9] . An important role in coronavirus infection pathophysiology is assigned to an inadequate immune system reaction and cytokine hyperproduction that can result in cytokine storm [11] . The mechanism of cytokine storm in COVID-19 is still not fully explored. SARS-CoV-2 spike protein binding activates various signal pathways, resulting in increased proliferation of T lymphocytes, macrophages, and NK cells [12, 13] as well as cytokine hyper production [14] .

Cytokine storm syndrome provokes DIC and cardiovascular dysfunction, and eventually, can lead to a multiple organ failure syndrome [7] . Liu et al. provide evidence that the following cytokines play a major role in severe COVID-19 symptoms: IL-6, IL-1β, IP10, and MCP-1. IL-6 and IL-1β are the main targets for monoclonal antibodies therapy [15] . IL-6 is the key cytokine in severe COVID-19 pathogenesis and cytokine storm progress. It is involved in Janus kinase-activated transmembrane transport of signals into the cell [16] . A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV)-infected pneumonia (China) published on 30th of January 2020 first recommended to monitor cytokines for faster recovery and decrease of mortality rate [17] .

High patient mortality rate is caused by the lack of a targeted antiviral therapy; therefore, a targeted treatment of the key pathogenic factors is of a major significance for patients' lifesaving [18] . Liu et al. claim that the most perspective and promising way is to inhibit the IL-6 [15] . A major retrospective study has shown that IL-6 is the predictor of adverse outcome and mortality in severe COVID-19 patients [19] .

IL-6 plays a key role in different lymphocyte population interaction and their activation. Animal models show that the inhibition of nuclear factor κB, which is also a key transcription factor of IL-6, or infecting animals with SARS-CoV strain with lacking envelope protein E that activates nuclear factor κB increase the infected animal survival rate through the decrease of IL-6 production [20] . These findings confirm the key role of IL-6 in pathogenesis of severe coronavirus infection and COVID-19 cytokine storm.

Therapeutic apheresis methods can benefit patients with severe COVID-19 symptoms by eliminating pro-inflammatory cytokines that play the key role in COVID-19 pathogenesis [15, 21] .

Therapeutic apheresis (EA) is a method of extracorporeal hemocorrection that plays an important role in patient management and treatment with different renal, hematological, rheumatological, and neurological disorders. During the procedure, different pathogenic components circulating in blood are eliminated from the blood of patients with various diseases [22] . Therapeutic apheresis methods are used to treat complex autoimmune diseases, allergic conditions, metabolic failures, sepsis and infectious diseases, hematological, hepatic and gastrointestinal diseases, neurologic conditions, and acute exogenous poisoning [23] . Therapeutic apheresis methods can be subdivided on the basis of what is the driving force of different molecule elimination: sorption and filtration [24] . A number of countries (China, Japan, USA, Italy, Russian Federation, etc.) have already included extracorporeal apheresis methods in COVID-19 treatment clinical guidelines [9, 11, 23, 25, 26] . Chinese clinical guidelines (expert recommendations on blood purification treatment protocol for patients with severe COVID-19) in particular describe in great detail the process of blood purification treatment for patients with severe COVID-19 with further patient monitoring [11] .

Extracorporeal apheresis methods application guidelines can also be found in ASFA-2019 (the American Society for Apheresis). According to ASFA-2019 guidelines, the possibility of plasma exchange in patients with infections fall under category III, degree 2B, which means that the optimal role of apheresis therapy in patient treatment is unknown, and currently, there is only a moderate evidence supporting the efficiency of this method [23] . Methods of AE were included into Russian Federation temporal clinical guidelines for new coronavirus disease (COVID-19) prevention, diagnosis, and treatment, version 14. Indications for use are progressive respiratory failure and/or multiple organ failure [9] .

The main effects of EA in severe COVID-19 patients are blocking the cytokine storm; reducing inflammation in lungs and improving respiratory function; improving kidney and liver functions; and most importantly, decreasing of the mortality rate of severe COVID-19 patients [27] .

It should be noted that to date, there has not been enough clinical data to fully understand the role of EA methods in the survival and mortality of COVID-19 patients. This is due to the lack of large randomized trials, and most information available is based on the description of a single clinical case or a series of cases, allowing to only assessing the individual patient's recovery rate and laboratory parameters before and after the procedure.

Currently, the most relevant SARS-CoV-2 variant of concern is Omicron (B.1.1.529 lineage), first identified in South Africa in November 2021 [28] . However, it should be noted that the Omicron variant is less clinically severe compared to the Delta variant. Patients with Omicron variants have fewer admissions to hospitals and especially to the intensive care department, and as a result, the mortality rate caused by Omicron is lower compared to other SARS-CoV-2 variants of concern (Delta variant, Gamma variant) [29] . It may be due to this that we were unable to find any information on the use of therapeutic apheresis for the treatment of Omicron variant, and most of the studies were related to Alpha, Beta, Gamma, and Delta variants.

Not much information was found about the possibility of using therapeutic apheresis in pediatric patients. Raina et al. [30] used CytoSorb absorber or oXiris filters when treating pediatric patients with COVID-19 who also required renal replacement therapy. A higher clearance was achieved through incorporation of CytoSorb or oXiris into the continuous kidney replacement therapy (CKRT) circuit. However, FDA has not yet officially approved the use of these devices for pediatric patients.

According to the latest published data, another important problem today is the development of a so called "post-COVID syndrome" or "long-COVID" in patients after COVID-19 infection recovery [31] . It is supposed that autoantibodies against the M1 acetylcholine receptors (AChR) [32] and autoantibodies against β1 and β2 adrenergic receptors (AdR) [33] play the key role in the pathophysiology of these syndromes. Therefore, more and more information is published about the possibility of including therapeutic apheresis methods, especially sorption methods, in the treatment of "post-COVID syndrome" [34, 35] .

Hemoadsorption is a type of extracorporeal detoxification therapy, when the target component is selectively extracted as a result of blood perfusion through the sorbent [36] . The active component of the adsorption column is a sorbent with granules with different size pores. When blood passes through the sorbent, the targeted molecules of certain size get absorbed by sorbent granules due to hydrophobic and ionic interactions [37] . This procedure does not have a high level of specificity, since removal of the molecules is only based on the size of these molecules [38] . However, there are also sorbents with a maximum level of specificity, where sorbent granules are linked with a specific ligand on their surface that have a molecule specific affinity from the circulating blood [39] . For example, hemoadsorption using an immobilized LPS-selective ligand makes it possible to remove only target molecules from blood -lipopolysaccharide molecules of Gram-negative bacteria [40] . Then the purified blood is returned to the patient. The schematic overview of hemoadsorption is given in Fig. 1 .

There are a lot of hemoadsorbers that have been proposed for hemoperfusion. For example, a disposable sterile cartridge of the HA 330 series (Jafron Biomedical, Co. LTD, China) removes excess inflammatory mediators, pro-inflammatory cytokines (IL-6, IL-10, TNF-alfa), metabolites and other pathogenic blood components, and residual drug concentrations. The neutral absorber, due to its macroporous structure and high specific surface area, binds excess proinflammatory factors from blood [41] . Cytosorb is a more expensive version of the similar type absorber (CytoSorbents Inc., Monmouth Junction, NJ, USA) [42] ; there is also a Russian device for hemoabsorption-Efferon CT (Russia) [43] .

The main advantages of hemoadsorption are the following: alongside of a cytokine removal, there is also an elimination of pathogen-associated molecular patterns or damage factors, substances that can provoke and maintain a generalized inflammatory response in the body [44] ; decrease in the level of vasopressors such as catecholamine in blood [45] ; reducing the need for anticoagulant therapy compared with other extracorporeal methods; decrease in the level of lactate in the blood serum [44] ; the highest selectivity compared to other ECH methods [36] . However, there are also some disadvantages: the need to control the doses of administered medications, as antibiotics are also removed during the procedure, for example, hydroxychloroquine and azithromycin due to the low molecular weight can be removed, but tocilizumab (148 kDa), antibodies (> 150 kDa), and other molecules of similar size are not removed [46] . Despite the higher selectivity of hemoadsorption compared to other methods, nonspecific binding of molecules to the sorbent is also possible. Patients may develop thrombocytopenia and leukopenia as side effects [47] . There is also a restriction on consumption of lipid or fat emulsions in food before the procedure [46] . Hemoadsoption is indicated for intensive care patients and patients in critical conditions (acute pancreatitis and peritonitis; respiratory distress syndrome; septic, burn, traumatic shock, and poisoning, etc.) and for patients with complex chronic diseases (allergies, especially with the phenomena of allergic diseases: intoxication, etc.) [48] .

Hemoadsorber used to remove inflammatory mediators from the bloodstream include CytoSorb, Cytosorbents, NJ, USA, and HA330, Jafron, China [37, 49, 50] . CytoSorb absorbers have become widely used for the COVID-19 treatment. In April 2020, FDA temporarily approved the emergency use of CytoSorb device for the treatment of cytokine storm in patients with COVID-19 [21] .

Prevention of cytokine storm syndrome associated with COVID-19 using EA treatments has been successfully used in China and Europe. As mentioned above, the most commonly used absorber is Cytosorb (Cytosorbents Inc, Monmouth Junction, NJ). CytoSorb hemoadsorption was also included in the national clinical guidelines in Italy [25] . In several observational studies and a randomized controlled trial involving patients with septic shock, CytoSorb was reported to reduce excess levels of inflammatory mediators, and required low need for vasopressors [51] [52] [53] [54] . CytoSorb demonstrated capacity to adsorb many of the mediators associated with severe COVID-19.

Stockmann et al. [55] noted that the removal of cytokines using CytoSorb in critically ill COVID-19 patients with suspected generalized inflammation and shock can be an excellent way of stabilizing hemodynamics and improving the clinical outcome. However, in a large open-label randomized controlled trial involving patients with severe COVID-19, they showed that the use of CytoSorb did not prevent the development of Vasoplegic shock; moreover, mortality level in the CytoSorb and control groups was almost the same at 78% and 73%, respectively [56] .

In an open-label randomized controlled study led by Supady et al. [57] , resulted indicated that CytoSorb decreased the level of IL-6 from 357.0 to 98.6 pg/ml. However, the number of survived patients after 30 days was 3 (18%) out of 17 in CytoSorb group and 13 (76%) out of 17 in control group (p = 0.0016). Thus, the authors concluded that an early cytokine adsorption in patients with severe COVID-19 and veno-venous ECMO did not reduce the level of IL-6 and had a negative effect on survival rate. Therefore, cytokine adsorption should not be used in the first days of ECMO for COVID-19 patients.

On the contrary, in March 2020, Damiani et al. [58] demonstrated successful experience of using the CytoSorb in the treatment of patients with COVID-19 at Papa Giovanni XXIII Hospital, Bergamo, Italy. There was a shown decrease in the concentration of cytokines with a significant decrease in IL-6, IL-8, IL-10, and IL-1β; clinical improvement was reported in most patients. Peng et al. [44] described a series Fig. 1 Adsorption process in the hemoadsorber. Blood goes through the hemoadsorption device, composed of specific porous sorbent beads. Molecules that are smaller than the pores in diameter are captured and removed from the bloodstream. The highest level of removing specificity is achieved by sorbent granules with synthetic ligands or antibodies that bind only targeted molecules from the bloodstream of cases where CytoSorb hemoadsorption was successfully applied to critically ill patients. CytoSorb also showed a great effect in the treatment of septic shock with a significant decrease in IL-6 levels [59] and in the treatment of cytokine storm [49] .

An important advantage of hemoadsorption compared to the other EA methods is its ability to integrate with most extracorporeal circulation systems, such as continuous renal replacement therapy (CRRT) or extracorporeal membrane oxygenation (ECMO), being a useful addition in combination with other EA methods [58] . For example, Dastan et al. [60] demonstrated the possibility of combining hemosorption using the HA330 cartridge (Jafron Biomedical Co., China) with continuous veno-venous hemofiltration (CVVH) treatment. This resulted in an increased saturation, improvement of CT scans, and a decrease of IL-1, IL-6, IL-8, and TNF-a. The authors also noted the benefits of adding tocilizumab to the complex therapy; however unlike hemoadsorption, it is a monoclonal antibody against the interleukin-6 receptor.

It should be noted that there is less data available on the use of Jafron absorbers than of CytoSorb; however, there are studies describing HA330 cartridges (Jafron Biomedical, China) in the COVID-19 treatment. Mikaeili et al. [61] conducted a comparative study to determine the effectiveness of the hemoadsorption procedure using HA 330 (Jafron Biomedical Co., China) compared to the standard COVID-19 therapy. Analyzing the obtained data, the authors concluded that there was a significant decrease in mortality among patients who had hemosorption with a P/F ratio above 75 (mortality rate of 84.7% with a P/F ratio < 75 vs. 15.4% with a P/F ratio ≥ 75, p = 0.02). It means that early initiation of hemoadsorption can be extremely effective in patients with severe COVID-19. Surasit et al. [62] conducted a prospective cohort study to compare 2 groups: patients with standard therapy and patients who received at least 3 hemoadsorption procedures using an HA 330 (Jafron Biomedical Co., China). The result of this study was that in the group of patients who had the hemoadsorption procedure, there was a marked improvement in laboratory parameters, and the 28-day mortality rate was significantly lower in the hemoperfusion group compared to the control group (6.67% vs 85.71%, p < 0.001). Thus, the authors noted that adding a hemoperfusion procedure at early stages of the disease may be beneficial in improving patient's condition and preventing death. However, it must be noted that the study results were influenced by external confounding factors associated with the initial state of the patients, as well as the small sample size.

In addition to CytoSorb and Jafron, Stephen et al. provided an example of a successful use of Seraph-100 Microbind Affinity Blood Filter column (Seraph-100; Exthera Medical Corporation, Martinez, CA) for the treatment of severe COVID-19. The results showed: restoration of hemodynamic parameters, temperature normalization, and a decrease in pro-inflammatory markers in the blood [63] . The authors claimed that this column was unique, as it directly bound SARS-CoV-2 and other pathogens due to specific sorbent particles, which mimics the natural heparin sulfate molecules of the endothelial cells [64] . At the same time, the column did not bind drugs [65] . Also, compared to other methods, there was no hypercoagulation reported, perhaps due to the internal heparin fragments present in the device. Previous reports of other hemoadsorbers that non-specifically bind endotoxins and cytokines suggested that hypercoagulation might be a significant problem [21, 66, 67] . This distinguishes Separah-100, for example, from CyroSorb, where there was no evidence of virus-binding properties. In this respect, Separah-100 has a selectivity advantage over the other absorption devices [63] .

According to Krenn et al., CytoSorb hemoadsorption is by far the most studied and clinically recommended method. The authors compared CytoSorb (CytoSorbents Inc., Monmouth Junction, NJ, USA), HA 330 (Jafron Biomedical Co., Guangdong, China), and Biosky MG (Biosun Medical Technology Co., Foshan, Guangdong, China). As for the latter, there are no specific recommendations available for its use. The pre-treatment process is more complicated in the case of HA-330, while CytoSorb does not require a prewash. Another attractive advantage of CytoSorb over HA-330 is its compatibility with other EA methods, whereas the incorporation of HA-330 is limited. It is worth noting, however, that Jafron and Biosky are less expensive than CytoSorb [68] . The price difference is quite impressive: CytoSorb is almost twice as expensive as HA 330 [69] . However, the capacity for continuous use of CytoSorb for several days negates this cost advantage [68] .

The data from a comparative study led by Magomedov et al. suggested that the use of Efferon -a Russian made absorber in addition to the standard therapy, in contrast to the standard therapy alone, lead to a statistically significant decrease in IL-6 and ferritin, while statistically there was no statistically significant differences in mortality between the two comparison groups [43] .

Thus, according to Koc et al., comparing the available data on the use of hemoadsorption for the treatment of severe forms of COVID-19, hemoadsorption therapy is an alternative method of treatment in critically ill patients with COVID-19: mortality, mean intubation time, and length of stay in the intensive care unit and hospital were 29%, 14.93 days, 17.21 days, and 31.7 days, respectively [70] .

Plasmapheresis is a method of separating plasma from blood cells with the return of the patient's own cells [65] . This technique is designed to remove pathogenic antibodies and lipoproteins. Plasmapheresis can be carried out either by membrane separation or centrifugation [71] . The main disadvantages are low selectivity, activation of complement, and leukocytes by an artificial membrane, and the need for a large vein catheter to obtain adequate blood flow [72] . Another important disadvantage is the need to replace the plasma volume. The low selectivity of plasmapheresis can lead to adverse side effects: plasmapheresis-associated coagulopathy [73] , hypogammaglobulinemia [27] , and hypotension [73] . All these factors must be taken into account during the procedure. Plasmapheresis based on the centrifugation technique is more common in the USA, whereas membrane separation is more popular in Russia, Germany, and Japan [74] .

The first plasma exchange filter was a flat parallel plate membrane (Centry TPE; Cobe) approved in the USA: plasma filters Prismaflex TPE-2000 (Baxter) and Plasmaflo OP-05 W (Asahi Kasei Medical Company Ltd. Japan). Their technical characteristics are very similar, but they differ from a conventional dialyzer intended for hemodialysis with higher selectivity [75] . In Russia, plasma filters PFM-800 consisting of flat "track" porous membranes manufactured by AO "Optika" and plasma filters manufactured by "Gemos-PFS" are used [76] .

Clinical indications for plasmapheresis are neurological, autoimmune diseases, when rapid removal of antibodies is necessary; in multiple sclerosis when there is no effect of glucocorticoids; opticomyelitis, neuropathy, systemic lupus erythematosus, and autoimmune hemolytic anemia [77] . Pathological factors that can be removed by plasmapheresis include autoantibodies, complement products, lipoproteins, immune complexes, cryglobulin, myeloma protein, ADAMTS-13, protein-bound toxins, platelets, and leukocytes [78] .

There are two medical terms that can be found in the literature: plasmapheresis and plasma exchange. Plasma exchange is plasmapheresis with a plasma exfusion volume of 70-150% of the circulating blood volume (CBV). Therefore, adjusted for the volume of plasma exfusion, these two terms can be considered synonymous. It should be noted that due to the widespread use of the plasma exchange method [36] , we will mainly describe the experience of plasma exchange use for the COVID-19 treatment; however, it must be remembered that the plasmapheresis method is the basis of plasma exchange.

Khamis et al. [79] conducted a small comparative study to assess the effect of therapeutic plasma exchange (TPE) in patients with severe COVID-19 compared with the control group. Authors concluded that there was a lower 14-day (0 versus 35%, p = 0.033) and 28-day (0 versus 35%, p = 0.033) mortality after TPE compared to the control group. However, all-cause mortality was only slightly lower in the TPE group than in the non-plasmapheresis group (9.1% vs. 45%; p = 0.055). Laboratory and ventilation parameters also improved after therapeutic plasma exchange.

Shi et al. demonstrated the successful use of PE for the treatment of severe COVID-19 patient. PE led to an improvement in the patient's condition, no further episodes of diarrhea, return of an appetite, improvement in CT, and an increase in PaO2/FiO2 [78] . Keith et al. used quadruple plasma exchange, after which the patient's general condition and lung radiographic picture improved [80] . Adeli et al. [81] and Ma et al. [82] described a series of clinical cases of successful plasma exchange method application. As a result, there was a recovery of patients, a decrease in the titer of anti-phospholipid antibodies and inflammatory markers, followed by withdrawal from mechanical ventilation [82] , and an increase in the survival of severe COVID-19 patients [81] . Duong-Quy et al. give an example of the successful use of therapeutic apheresis in a pregnant woman at 17 weeks gestation admitted to the intensive care unit with severe COVID-19. The patient received 3 cycles of plasma exchange, and as a result, her condition improved and the level of pro-inflammation cytokines normalized. Authors says that plasma exchange therapy may be very beneficial in situations when other therapies are failing. The possibility of using plasma exchange in pregnant is possible because of the high level of the procedure's safety [83] . The plasmapheresis can also be used for the combined therapy of COVID-19 complications. For example, successful experience in the treatment of COVID-19-associated meningoencephalitis in ventilated patients was demonstrated [84] .

Patidar et al. tried to explore the main advantages and disadvantages of PE treatment. There are a lot of data confirming the effectiveness of plasma exchange in sepsis, and it is clear that this method can be useful during the initial stages of the disease to prevent the syndrome of multiple organ failure. However, the clinical evidence for its effectiveness in COVID-19 is extremely low. In addition, the method has no absolute contraindications that is why there is a widespread use of plasma exchange therapy [85] .

It is not always possible distinguish which treatment led to a particular result. That is why various comparative studies are required. For example, Luo et al. [86] tried to compare the effects of tocilizumab therapy and plasma exchange. After plasma exchange, in contrast to tocilizumab, there was a pronounced decrease in the levels of CRP, IL-6, reconstitution of the number of lymphocytes, and return of PTI to the initial level. Thus, the authors concluded that plasma exchange was more preferable in patients with severe COVID-19.

Nowadays, there are a lot of data on the combination of various EA techniques to achieve the best results. Yang et al. noted that plasmapheresis could be performed both as a separate procedure and in combination with other methods of blood purification, including immunoadsorption, twovolume plasma filtration, continuous plasma filtration and adsorption, multifiltration systems, continuous veno-venous hemofiltration, and slow continuous ultrafiltration [11] .

Selective plasma filtration (SPF) is a semi-selective extracorporeal hemocorrection method from the group of therapeutic apheresis membrane technologies [36] . This method is based on the principle of water molecules and substances dissolved in it being transferred through a semi-impermeable membrane [87] . The main driving force in this case is the pressure gradient. It can be useful for removing various medium-and low-molecularweight components (cytokines or immunoglobulin group G [87] , bilirubin, bile acids, urea [88] ), the size of which is approximately equal to the size of an albumin molecule, from the blood, while maintaining bigger components [36] (immunoglobulins M, coagulation factors and fibrinogen [89] ). Special devices, which are called plasma fractionators, are used for the SPF procedure. The most popular fractionators today are Evaclio M (Kawasumi Laboratories Inc., Japan) [90] . It noteworthy, that until 2005, this type of plasma fractionators were called Evacure, and they were used exclusively in Japan. Later, SPF method and plasma separators became widely used all over the world, and from that on have been produced under the trade name Evaclio [88] . Separators are divided into different types depending on the pore sizes and each separator has its own level of selectivity towards certain molecules. The marker molecule for SPF is the albumin molecule (66 kDa) [90] . A simplified scheme of plasma filtration is shown in Fig. 2 .

The main feature of SPF is the need to restore a plasma volume equal to the removed blood filtrate (fresh frozen plasma or albumin are used). Due to the structural features of the filter, all the necessary coagulation factors remain in the blood stream, so there is no need to add them [87] . Thus, the main advantages of SPF are a large extraction volume (up to 10 l) and minimal protein loss. Depending on the goals and objectives of the therapy, filters with different pore diameters can be selected [91] . The main disadvantage of the procedure is the semi-selectivity of the method, since only the pore size can be controlled [90] .

Clinical indications for the SPF procedure on EVA-CLIO are sepsis, liver failure, rhabdomyolysis, multiple myeloma (Bence-Jones), metabolic syndrome, and focal segmental glomerulosclerosis [23, 92] . The ability to remove IgG using the SPF allows the use of EC-4A fractionators for various immunological disorders. The use of SPF is also effective for the treatment of autoimmune blistering skin disorder and thrombocytopenia [87] . The experience of using SPF in transplantation as a pre-transplantation preparation for AB0-incompatible donor and recipient has also been described [93] . Nakamoto et al. give examples of the successful use of SPF as part of the complex therapy of autoimmune conditions and kidney diseases [94] . Nakae et al. demonstrated the possibility of using the SPF method for the complex treatment of thrombocytopenia [95] . Removes components from the blood of medium to low molecular weight; the size of the molecules is approximately equal to the size of an albumin molecule. Larger components (for example coagulation factors) remain in blood. The pore size allows controlling the selectivity of the method [36] -High-molecular compounds, such as coagulation factors and IgM, do not pass through the pores of the filter; -Large volume of plasma passing through the column; -"Protein-preserving" procedure -minimal loss of albumin [90] Removes cytokines from plasma due to their small molecular weight: they pass through the pores of the filter [ 

This method resembles the plasmapheresis method; however, in the case of SPF, it is possible to select the appropriate filter pore size, thereby controlling selectivity [90] . However, there are not much data on the use of this method for the COVID-19 treatment. Samoylov et al. proposed introducing SPF, using Evaclio 2C20 plasma fractionator to treat patients with severe COVID-19. According to the author, this would effectively remove inflammatory mediators circulating in blood, while almost completely preserving large protein molecules, such as immune globulins and coagulation factors [96] . Avetisyan et al. reported a successful use of SPF as a part of a complex therapy of a patient with a severe form of COVD-19. Selective plasma filtration was carried out using Evaclio 2C separator. The results of the procedure were temperature normalization, a decrease of CRP levels more than in a half, a decrease in liver enzymes (ALT and AST), and an absence of a clinically significant increase in creatinine levels [97] . Avetisyan et al. did a comparative study of hemoperfusion and SPF methods in the context of their use for COVID-19 treatment. The research indicated that SPF was more beneficial for patients with hepatic and renal dysfunction, signs of multiple organ failure. It was noted that the selectivity of this method made it possible to remove predominantly hydrophilic molecules with a molecular weight of less than 65 kDa. The total loss of albumin in that case was 30% due to the use of an appropriate filter size [97] .

Selective plasma filtration may also be part of a combination of EA methods used to treat COVID-19. For example, Lin et al. [98] described a clinical case when highvolume hemofiltration and the subsequent performance of three plasma filtration procedures were used. The authors described a significant improvement of patient's condition after plasma filtration. Zashezova et al. [99] demonstrated a successful application of a combination of cytokine sorption using an HA330 absorber (Jafron) and selective plasma filtration using an Evaclio 2C plasma filter. The combination treatment resulted in the temperature normalization and positive dynamics of laboratory parameters, primarily CRP and IL-6. A brief description and application of EA methods for COVID-19 treatment are presented in Table 1 .

Methods of extracorporeal apheresis are becoming an important addition to combination therapy for COVID-19. EA methods demonstrate the greatest efficiency for patients with severe forms of COVID-19, when there is a threat of the cytokine storm development. Among all methods of apheresis in COVID-19 treatment, the methods of hemoadsorption, plasma filtration, and plasma exchange are most widely used.

Based on the available published data, it can be concluded that hemoadsorption using Cytosorb (Cytosorbents Inc, Monmouth Junction, NJ) and HA 330 (Jafron, Biomedical Co, China) is the most widely utilized method. In view of a larger evidence-based data for CyroSorb and the possibility of its use in patients with septic shock, Cyto-Sorb is more preferable to remove mediators responsible for the development of a cytokine storm from the circulating blood of patients. However, as shown by comparative studies, HA330 can also be used for treatment of severe forms of COVID-19, significantly reducing mortality compared to control groups. Less information can be found regarding Seraph-100 Microbind Affinity Blood Filter columns (Seraph-100; Exthera Medical Corporation, Martinez, CA) and Efferon TsT (Russia).

A large number of clinical cases are also available, describing the successful use of a plasma exchange method for treatment of patients with severe forms of COVID-19. Selective plasma filtration method, despite being rarely mentioned in the literature, also showed good results as part of a combination treatment of severe forms of COVID-19.

Perhaps, due to a lesser severity of symptoms caused by a new SARS-CoV-2 variant Omicron (B.1.1.529 lineage) and fewer admissions to hospitals, especially to the intensive care unit, there were no current studies available, describing the use of therapeutic apheresis for the treatment of Omicron variant, but only focused on Alpha, Beta, Gamma, and Delta variants.

As more people start to experience the so called "post-COVID syndrome" or "long-COVID", more studies focus on the application of therapeutic apheresis methods, especially sorption methods, in the treatment of "post-COVID syndrome".

BNL was supported by the Kazan Federal University Strategic Academic Leadership Program (PRIORITY-2030).

The authors declare no competing interests.

This article does not contain any studies involving human participants or animals performed by any of the authors.

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Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome

Review: Cytokine storm syndrome: Looking toward the precision medicine era

Clinical characteristics of coronavirus disease 2019 in China

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Coronavirus disease 2019 ( COVID-19) : situation report

Temporary methodological recommendations: Prevention, diagnosis and treatment of new coronavirus infections (COVID-19), version 14. The ministry of health of the russian federation

Coronavirus disease 2019 ( COVID-19) : situation report

Expert recommendations on blood purification treatment protocol for patients with severe COVID-19. Chronic Diseases and Translational Medicine

Preparing for the next pandemic

Mapping the innate signaling cascade essential for cytokine storm during influenza virus infection. Proceedings of the National academy of Sciences of the United States of America

COVID-19: A new virus, but a familiar receptor and cytokine release syndrome

Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)?

Analysis of serum cytokines in patients with severe acute respiratory syndrome

A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia

Clinical observation and management of COVID-19 patients // Emerg. Microbes Infect

Clinical course and risk factors for mortality of adult in patients with COVID-19 in Wuhan, China: A Retrospective Cohort Study

Inhibition of NF-kappaB-mediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival

Extracorporeal blood purification and organ support in the critically ill patient during COVID-19 pandemic: Expert review and recommendation

Introduction and overview of therapeutic apheresis

Guidelines on the use of therapeutic apheresis in clinical practice: Evidence-based approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue

Clinical application of transfusion hemocorrection modalities

Coronavirus epidemic and extracorporeal therapies in intensive care: Si vis pacem para bellum

Labor and Welfare new coronavirus infectious disease countermeasures promotion headquarters

Effect of artificial liver blood purification treatment on the survival of critical ill COVID-19 patients. Artificial Organs

Emerging variants of SARS-CoV-2 and novel therapeutics against coronavirus (COVID-19)

COVID-19 severity from Omicron and Delta SARS-CoV-2 variants

Blood filters in children with COVID-19 and acute kidney injury: a review. Therapeutic apheresis and dialysis : Official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the

Track COVID-19 sickness, not just positive tests and deaths

Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome

Antibodies to beta adrenergic and muscarinic cholinergic receptors in patients with chronic fatigue syndrome

Immunoadsorption to remove ss2 adrenergic receptor antibodies in chronic fatigue syndrome CFS/ME

Myalgic encephalomyelitis/ chronic fatigue syndrome: Efficacy of repeat immunoadsorption

Extracorporeal hemocorrection: terminology, language correspondences: Methodological recommendations of NP National Society of Specialists in the Field of Hemapheresis and Extracorporeal Blood Correction

Removal of humoral mediators and the effect on the survival of septic patients by hemoperfusion with neutral microporous resin column

Immunosorption in the treatment of autoimmune diseases

Hemosorption by a column adsorber based on hyper-crosslinked styrene-divinylbenzene copolymer with immobilized lipopolysaccharide-selective ligand in combined intensive care of lung cancer-related postoperative acute lung injury (case report)

Efficacy of HA330 hemoperfusion adsorbent in patients followed in the intensive care unit for septic shock and acute kidney injury and treated with continuous venovenous hemodiafiltration as renal replacement therapy

Efficacy and safety of a novel adsorber for lps-selective hemosorption

Hemoperfusion with the Efferon CT extracorporeal adsorbers containing mesoporous styrene-divinylbenzene copolymer (SDC) in patients with severe COVID-19

Hemoperfusion with CytoSorb® in critically ill COVID-19 Patients

Extracorporeal cytokine elimination as rescue therapy in refractory septic shock: A prospective single-center study

What have we learned about the use of cytosorb adsorption columns?

Sorbents in acute renal failure and end-stage renal disease: Middle molecule and cytokine removal

Biospecific hemosorption on the apparatus AMPld-TT (HEMOFE-NIX): Guidelines

Cytosorb filter: An adjunct for survival in the COVID-19 patient in cytokine storm? a case report

Cytosorb adsorption during emergency cardiac operations in patients at high risk of bleeding. The analysis of thoracic surgery

Extracorporeal cytokine elimination as rescue therapy in refractory septic shock: A prospective single-center study

Hemoadsorption by CytoSorb in septic patients: A case series

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

Extracorporeal cytokine adsorption in septic shock: A proof of concept randomized, controlled pilot study

CytoResc trial investigators. CytoResc -"CytoSorb" rescue for critically ill patients undergoing the COVID-19 cytokine storm: A structured summary of a study protocol for a randomized controlled trial

CytoSorb rescue for COVID-19 patients with vasoplegic shock and multiple organ failure: A prospective, open-label, randomized controlled pilot study

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

Extracorporeal cytokine hemadsorption in severe COVID-19 respiratory failure

Cytokine blood filtration responses in COVID-19

Continues renal replacement therapy (CRRT) with disposable hemoperfusion cartridge: A promising option for severe COVID-19

The early start of hemoperfusion decreases the mortality rate among severe COVID-19 patients: A preliminary study

The efficacy of early additional hemoperfusion therapy for severe COVID-19 patients: A prospective cohort study

Treatment for severe coronavirus disease 2019 with the Seraph-100 microbind affinity blood filter

In vitro elimination of anti-infective drugs by the Seraph 100 microbind affinity blood filter

GiViTI: Gruppo Italiano per la Valutazione degli Interventi in Terapia Intensiva (Italian Group for the Evaluation of Interventions in Intensive Care Medicine) is an independent collaboration network of Italian Intensive Care units: Efficacy of coupled plasma filtration adsorption (CPFA) in patients with septic shock: A multicenter randomised controlled clinical trial

Blood purification and mortality in sepsis: A meta-analysis of randomized trials

Hemoadsorption for blood purification-incomparability of clinically available procedures

Cytokine adsorption devices for treating respiratory failure in people with COVID-19

Literature review of hemadsorption therapy in severe COVID-19 Cases: A narrative review

The role of plasmapheresis in critical illness

Plasmapheresis. Technical aspects and indications

The safety of heparins in end-stage renal disease

Therapeutic plasma exchange using membrane plasma separation

Available removal systems: State of the art

Therapeutic apheresis in myasthenia gravis

A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease

Successful treatment with plasma exchange followed by intravenous immunoglobulin in a critically ill patient with COVID-19

Therapeutic plasma exchange in adults with severe COVID-19 infection

The successful use of therapeutic plasma exchange for severe COVID-19 acute respiratory distress syndrome with multiple organ failure

Published by Polish Archives of Internal Medicine https:// www. resea rchga te. net/ profi le/ Jamsh id-Vafae imane sh/ publi cation/ 34121 9961_ Using_ thera peutic_ plasma_ excha nge_ as_a_ rescue_ thera py_ in_ CoVID-19_ patie nts_a_ case_ series/ links/ 5eb47 84492 851cd 50da1 206f/ Using-thera peutic-plasma-excha nge-as-a-rescuethera py-in-CoVID-19-patie nts-a-case-series

Potential effect of blood purification therapy in reducing cytokine storm as a late complication of critically ill COVID-19

The use of therapeutic plasma exchange in the treatment of a pregnant woman with COVID-19 induced acute respiratory distress syndrome

Plasmapheresis treatment in COVID-19-related autoimmune meningoencephalitis: Case series

Understanding the role of therapeutic plasma exchange in COVID-19: Preliminary guidance and practices

Clinical observation of 6 severe COVID-19 patients treated with plasma exchange or tocilizumab

Selective plasma exchange

Plasma Separator Evaclio. Kawasumi Laboratories

Estimation of efficiency selective plasmofiltration at the mechanical jaundice

Comparison of selective plasma exchange and plasmadialfiltration with MARS and Prometheus systems in the treatment of liver failure

Features of complex treatment of patients with new coronavirus infection (Covid-19): Methodological recommendations for the management of in-site patients

The Japanese Society for Apheresis clinical practice guideline for therapeutic apheresis

Efficacy of selective plasma exchange as pre-transplant apheresis in ABOincompatible kidney transplantation

Our approaches to selective plasma exchange. Recent advances in dialysis therapy in Japan

Selective plasma exchange for critically ill patients accompanied with thrombocytopenia

A clinical case of successful application of a new treatment method for severe COVID-19

Combined extracorporeal blood purification by means of cytokine sorption and selective plasma exchange in patients with severe COVID-19 -clinical case series, from Russia. Jafron Oversea clinical cases collection

Application of plasma exchange in association with higher dose CVVH in cytokine storm complicating COVID-19

CT for dynamic changes in the case of covid-19: Therapy using cytokine sorption and selective plasma filtration

Hemoadsorption with CytoSorb®

Hemoadsorption by CytoSorb in septic patients: a case series

Historical perspective on plasmapheresis

Perioperative therapeutic plasmapheresis

Massive transfusion