Severe coronavirus disease 2019 (COVID-19) illness has been associated with high levels of cytokines — small proteins in the blood that both promote and control inflammation.1-3 Instead of enhancing the immune response to the infection, excessive levels of cytokines may result in a “cytokine storm” that can lead to systemic inflammatory response syndrome, acute respiratory distress syndrome, acute kidney injury, multiple organ dysfunction, and death.1,4-6
Cytokine storms have also been associated with severe illness in past outbreaks of infectious respiratory viruses, including the 1918 influenza pandemic, H5N1 influenza (avian influenza), Middle Eastern Respiratory Syndrome (MERS), and severe acute respiratory distress (SARS).1,3,7,8
Technologies that filter the blood to reduce levels of cytokines — sometimes also referred to as therapeutic apheresis — may help control the inflammatory response and improve the treatment of critically ill patients with COVID-19.
How It Works
Various types of extracorporeal blood purification systems are available. All of these use a blood pump to remove a patient’s blood, separate blood components or remove particular substances (such as toxins or antibodies), and return the blood to the patient.9,10 Blood purification is used in addition to standard care.11 The focus of this article is on hemoperfusion and hemofiltration devices, but other techniques, such as plasmapheresis (replacing plasma with fresh frozen plasma or albumin), may also be used.7,12
- Hemoperfusion — use of a sorbent cartridge or column to remove certain agents from the blood.6,7 Examples of hemoperfusion devices include: PMX (also known as Toraymyxin), CytoSorb, Jafron HA380, and the D2000 Adsorption Cartridge.
- Hemofiltration — use of an adsorptive filtering membrane to remove inflammatory mediators.7 An example of a hemofiltration membrane device is oXiris (an AN69 membrane).
The PMX (Toraymyxin) cartridge consists of composite woven polystyrene fibres coated with polymyxin B.12 The polymyxin B has electrochemical properties that remove endotoxins from the blood. Removal of endotoxins also reduces the release of cytokines and other inflammatory agents.13,14 The manufacturer’s recommended protocol for hemoperfusion is two two-hour procedures over a 24-hour period.14
The CytoSorb cartridge is filled with biocompatible polymer beads about the size of grains of salt. The pores in each bead are sized to allow larger components, such as blood cells, to pass around the beads and smaller components, such as electrolytes, to pass through. However, hydrophobic substances, such as cytokines, are trapped inside the beads and removed from the bloodstream.15 Blood may be continuously recirculated through the filtering system until a replacement cartridge is needed (for up to 24 hours). The manufacturer recommends an initial three-day-course of therapy for patients with severe COVID-19, with a cartridge change every 12 hours on day one and every 24 hours on days two and three.16 The higher the concentration of cytokines in the blood, the faster cytokine levels are reduced.11,12 After the third day of treatment, patients should be assessed to determine whether there are signs of benefit, in which case CytoSorb treatment can continue until their conditions are stable. If no benefit is apparent at 72 hours, the manufacturer suggests that the treatment should be discontinued.16
The Jafron adsorption cartridge consists of a “neutral, macroporous resin,” with a large surface area that adsorbs inflammatory agents, including cytokines.17 Instructions for the Jafron hemoperfusion cartridges recommend a three-day-course of therapy, with two treatments (cartridges) in the first 24 hours and one treatment on days two and three.17,18
The D2000 plasma Adsorption Cartridge consists of a proprietary blend of resins intended to remove cytokines, toxins, and metabolic wastes from plasma in patients with acute respiratory distress syndrome, sepsis, liver failure, drug overdoses, and other conditions that involve an inflammatory response.19 According to the FDA Emergency Use Authorization notification, the D2000 adsorbents can remove statistically significant levels of proinflammatory cytokines.20
The oXiris filter consists of a multi-layer, high adsorption, polymer membrane (AN69) that can adsorb substances such as certain toxins, as well as cytokines, and excess fluid.1,21,22 OXiris also has a heparin coating that allows it to be used without anticoagulation in patients at increased risk of bleeding.1
With some devices, such as the CytoSorb and the Jafron devices, the filter cartridge can be used with standard hospital equipment, such as dialysis equipment, hemoperfusion pumps, continuous renal replacement therapy, or extracorporeal membrane oxygenation.15-17 Other devices are designed for use with certain systems; for example, oXiris is intended to be used only with Baxter blood purification units (PrisMax and Prismaflex).21 The D2000 cartridge can be used with validated existing plasma separation platforms, including plasma exchange and continuous renal replacement therapy systems; however, under the FDA Emergency Use Authorization in the treatment of patients with COVID-19, it is being used exclusively with the Spectra Optia Apheresis System.19,23
Who Might Benefit?
Based on early reports from China, approximately 80% of people who contract COVID-19 will have only mild to moderate symptoms of the disease, while about 14% will experience more severe illness, and an estimated 6% will be critically ill, requiring intensive care.24 Reports on clinical experience with COVID-19 in China indicate from 5% to 10% of intensive care patients received extracorporeal therapies, such as continuous renal replacement, hemoadsorption, and hemoperfusion.25
Critically ill patients with COVID-19 have a cascade of immune system reactions, which include the release of cytokines into the blood.26 Sometimes referred to as systemic inflammatory response or cytokine release syndrome, or a “cytokine storm,” this response is associated with elevated levels of inflammatory agents, such as tumour necrosis factor alpha and interleukins.26-32
In some patients, the immune response becomes overwhelming, attacking healthy tissue, organs (such as the lungs, liver, and kidneys), and blood cells.28,29 This may cause respiratory failure, organ failure, and shock.11 One US estimate is that 20% to 30% of patients with severe COVID-19 and respiratory symptoms may experience a cytokine storm.29,33 Reducing levels of cytokines may lower the inflammatory response and, potentially, reduce the risk of morbidity and death.11,33
Availability in Canada
- The PMX (Toraymyxin) hemoperfusion cartridge (Spectral Medical Inc./Baxter) received an Interim Order from Health Canada, allowing its use for patients with COVID-19 who have acute respiratory failure and hypotensive shock.13 PMX (Toraymyxin) initially received a Health Canada medical device licence in 2003.34
- The oXiris Blood Purification Filter (Baxter) received a Health Canada medical device licence in 2009.34 In April 2020, oXiris received US FDA Emergency Use Authorization for use in reducing proinflammatory cytokine levels in patients with severe COVID-19 who are receiving intensive care, including those receiving continuous renal replacement therapy.21
Other systems are commercially available elsewhere but not currently in Canada include:
- CytoSorb (CytoSorbents Inc.) — has a CE mark for use in 11,33 and received US FDA Emergency Use Authorization for the emergency treatment of COVID-19.16 According to the manufacturer, more than 750 COVID-19 patients have been treated with CytoSorb in China, Germany, and Italy.35 CytoSorbents has prepared a rationale for using CytoSorb therapy in critically ill COVID-19 patients where elevated cytokines are present.36
- Jafron HA380 hemoperfusion cartridge (Jafron Biomedical Co.) — is available in China and has a CE mark for use in Europe, including the use for COVID-19 rescue therapy.4,11,17
- The Spectra Optia Apheresis System (Terumbo BCT. Inc.) — received a Health Canada medical device licence in 2008.34 The US FDA issued an Emergency Use Authorization (for use during the COVID-19 pandemic) for the Spectra Optia Apheresis System with the D2000 Adsorption Cartridge(Marker Therapeutics AG).23 The D2000 Adsorption Cartridge has a CE mark for use in Europe.11 The D2000 cartridge does not currently have a Health Canada medical device licence, but the manufacturer plans to apply for one in the near future (Sam Haddaway, Marker Therapeutics AG, Zug, Switzerland: personal communication, Jun 2, 2020).
What Does It Cost?
Spectral Medical recently announced the PMX (Toraymyxin) cartridges will be provided free of charge for COVID-19 patients.13
The 2020 UK NICE‒National Institute for Health and Care Excellence briefing on cytokine adsorption devices estimated the cost of the CytoSorb cartridge as £920 per single-use cartridge.11,33 A three-day treatment with CytoSorb, as recommended by the manufacturer, would require four cartridges.16
The Health Technology Wales scoping and the NICE briefing both cited the cost of the Jafron HA380 hemoperfusion cartridge as £450 for each single-use cartridge.4,11 The manufacturer also recommends a three-day course of therapy, with two treatments (cartridges) used in the first 24 hours and one cartridge treatment each on days two and three.17
The D2000 column costs US$2,000 per column, and patients typically receive two to five columns administered once per day for two to three hours per treatment (Sam Haddaway: personal communication, June 2, 2020).
Recent Canadian and international guidelines on therapies for COVID-19 have not included blood purification technologies.11,37-39 However, some treatment protocols from clinicians in China and Europe have included the use of cytokine adsorption technologies to manage a cytokine storm.4,6,40
Cytokine storms can happen rapidly and clinicians are beginning to test for indicators of this condition using tests for blood ferritin, elevated C-reactive protein, and biomarkers of acute kidney injury.6,29 A recent letter to The Lancet highlighted the importance of looking for signs of cytokine storm, including laboratory test results to assess the “Hscore” (indicators of inflammation), and considering appropriate immunomodulatory treatments.41
A recent consensus statement from critical care specialists in China proposes a four-step process for the use of blood purification treatments in patients with severe COVID-19.42 The steps are:
- Assess whether the patient requires blood purification. Patients who may benefit from blood purification include those with kidney disorders, SARS, sepsis, liver failure, or multiple organ dysfunction syndrome.
- Prescribe the type of blood purification treatment. This depends on the treatment goal. For example, to remove inflammatory mediators, recommended treatment modalities are various modes of hemofiltration, blood or plasma perfusion, adsorption, or continuous plasma filtration. For acute liver failure, however, plasma exchange is recommended.
- Patient monitoring and treatment adjustment. For example, monitoring vital signs, fluids, electrolytes, anticoagulation, and lung imaging.
- Determining when to discontinue blood purification therapy. The authors note that there is no consensus for this step, but, in general, to discontinue blood purification therapy when vital signs, fluids, urine output, and inflammatory response have improved.42
What is the Evidence?
A 2020 Medtech innovation briefing by NICE in the UK appraised the evidence on cytokine adsorption for the treatment of respiratory failure in patients with COVID-19.11 The evidence reviewed consisted of one observational study and numerous case reports (a total of 56 patients with COVID-19). Most of the evidence included was published on the manufacturers’ websites and consisted of non‒peer-reviewed case reports and one observational study.11 The briefing concluded that, based on limited, low-quality evidence, cytokine adsorption devices can be used safely as an adjunctive therapy to reduce levels of cytokines, which may improve lung function.11 However, the varying treatment protocols used and the quality of the available studies limit the generalizability of these conclusions.11
A 2020 scoping report from Health Technology Wales found no systematic reviews on the use of cytokine adsorbers in people with COVID-19.4 However, it found two systematic reviews on blood purification treatments for patients with sepsis.7,43 Based on low-quality evidence, blood purification to remove endotoxins appeared to improve mortality, but whether this might also benefit patients with COVID-19 is not yet known.4
The Health Technology Wales scoping report included information from an unpublished manuscript provided by the manufacturer of the Jafron device.4 This reported on 47 patients with severe COVID-19 in a non-randomized study in China.4 In the study, 26 of the patients received the hemoadsorption treatment in addition to standard treatment. In the hemoadsorption group, at 72 hours, blood cytokine levels were lower and oxygen levels were improved. The mortality rate at 28 days was lower in the hemoadsorption group (15.38%) compared to the patients who received only standard treatment (47.62%).4 Additional evidence on the Jafron adsorption cartridges was included in the more recent NICE briefing.11 The additional evidence was from mainly unpublished case reports of 21 patients treated in five different centres.11
A brief letter to the editor reported on three critically ill patients with COVID-19 in China who received blood purification to reduce cytokine storm.5 Two of the patients received treatment with the oXiris filter system. Although one of the patients died, the authors speculate that an earlier reduction of cytokine storm through blood purification may be beneficial for selected patients.5
Blood purification technologies are somewhat unselective and they may inadvertently remove beneficial agents — such as antibiotics, anticoagulants, or other drugs — and nutrients from the blood.6,12,15,18,40 As patients with COVID-19 are at increased risk for blood clots, ensuring anticoagulation therapy is adequate will be important.11 Changing the timing of medication administration (to after blood purification treatment) or increasing the drug dosage accordingly may resolve this issue.15
A 2019 systematic review of blood purification techniques in patients with sepsis cautioned that the “unspecific removal of cytokines” may also negatively affect the healthy immune response and could potentially result in worse patient outcomes.7
The CytoSorb FDA documents note that little information is available on the potential removal of antiviral drugs during the treatment process.16 However, because of their larger size, the removal of drugs such as tocilizumab, other biologics, and convalescent plasma antibodies is not expected to occur.16
Rarely, patients may experience an allergic reaction or anaphylaxis that requires treatment.16 Other potential complications could be related to the catheter and insertion of the blood line, or from the use of anticoagulants.6,12 In addition, the overuse of blood filtration could exacerbate hypotension and decrease cardiac output.6
Issues to Consider
Individuals have different “inflammatory phenotypes” and levels of cytokines in their blood.6 Currently, it is not possible to identify which severely ill patients could benefit from blood purification treatments.6,44
The optimal timing for initiating blood purification is not yet known, although some authors suggest that early application in severely ill patients may be most effective.1,2,6,12
UK specialists’ comments on the use of cytokine adsorption (for patients with sepsis and with COVID-19) noted that, potentially, the use of cytokine adsorption could increase intensive care unit capacity and reduce costs (for example, if this treatment reduced the length of hospital stay, and reduced the use of vasopressor drugs or biological therapies). However, evidence to support this is not yet available.11,33 A 2018 review of extracorporeal blood purification in sepsis also noted that evidence on the impact on mortality and length of intensive care unit or hospital stay is both “limited and somewhat conflicting.”12
The Health Technology Wales scoping report noted an ongoing German study of cytokine hemoadsorption for patients with severe COVID-19 pneumonia.4,45 This study is estimated to be completed in November 2020.45 Several other clinical trials have been initiated.11 For example, in Spain, a pilot study began in March 2020 to assess cytokine filtration in COVID-19 patients with acute respiratory distress syndrome.46 The D2000 Adsorption Cartridge FDA Emergency Use Authorization allows Marker Therapeutics AG and Terumo BCT to treat up to 2,000 patients with COVID-19 at up to 15 US sites. The first patients have been treated. In parallel, the companies are collecting patient data under an approved institutional review board protocol to support an approval submission to the FDA (Sam Haddaway: personal communication, Jun 9, 2020).47,48
A Canadian study at the Lawson Health Research Institute in London, Ontario, is assessing the use of slow (or sustained), low-efficiency daily dialysis and a leucocyte modulation device (L-MOD) to reduce inflammation in patients with severe respiratory distress syndrome due to COVID-19.49 This study is expected to be completed in January 2021.49
CytoSorbents’ website notes that a new version of CytoSorb — CytoSorb-XL — is in development.50 In addition to cytokine removal, CytoSorb-XL will remove endotoxins, for example, for use in the treatment of gram-negative bacterial infections.50
Drug therapies currently used for other conditions, such as monoclonal antibodies for immune suppression (for example, tocilizumab [Actemra]), are also being investigated as drugs that may block IL-6 and other proinflammatory cytokines in COVID-19 patients.27,29,31,32,40 Currently, in a phase III clinical trial, the Janus kinase inhibitor (brand name Jakafi) is also intended to reduce cytokine storm in COVID-19 patients with severe pneumonia.41,51
An extracorporeal blood filtration device with US Emergency Use Authorization for patients with severe COVID-19, the Seraph 100 Microbind Affinity Blood Filter (ExThera Medical Corporation), removes viruses and bacteria from the blood, thereby also reducing inflammatory mediators.52
Researchers in China have developed an artificial liver blood purification system that is also intended to remove cytokines in critically ill patients with COVID-19.3
Therapeutic plasma exchange is also being explored for the treatment of patients with severe COVID-19 illness. This is another mechanism for removing cytokines and one that is sometimes used in combination with convalescent plasma therapy.53-55
Currently, there is limited evidence on the use of blood purification using cytokine adsorption in patients with severe COVID-19 illness.4,6,11 As with many treatments for COVID-19, most of the available evidence is based on earlier studies in patients with other infectious respiratory diseases and sepsis.4,12 Whether this evidence is generalizable to COVID-19 patients is not yet clear.4 Hopefully, trials that are now underway will help to address these evidence gaps.
Author: Leigh-Ann Topfer
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- Zhang Y, Yu L, Tang L, et al. A promising anti-cytokine-storm targeted therapy for COVID-19: the artificial-liver blood-purification system. Engineering (Beijing, China). 2020 Mar 20 [Epub ahead of print].
- Cytokine adsorbers for the treatment of cytokine storm in people with severe coronavirus infection. Cardiff (UK): Health Technology Wales; 2020: https://www.healthtechnology.wales/wp-content/uploads/2020/04/TER201-Jafron-cytokine-adsorber.pdf. Accessed 2020 Apr 29.
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- Ronco C, Bagshaw SM, Bellomo R, et al. Extracorporeal blood purification and organ support in the critically ill patient during COVID-19 pandemic: expert review and recommendation. Blood Purif. 2020 May 26 [Epub ahead of print].
- Putzu A, Schorer R, Lopez-Delgado JC, Cassina T, Landoni G. Blood purification and mortality in sepsis and septic shock: a systematic review and meta-analysis of randomized trials. Anesthesiology. 2019;131(3):580-593.
- Coperchini F, Chiovato L, Croce L, Magri F, Rotondi M. The cytokine storm in COVID-19: an overview of the involvement of the chemokine/chemokine-receptor system. Cytokine Growth Factor Rev. 2020;53:25-32.
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- Cytokine adsorption devices for treating respiratory failure in people with COVID-19. Medtech innovation briefing. London (UK): National Institute for Health and Care Excellence (NICE); 2020: https://www.nice.org.uk/advice/mib217/resources/cytokine-adsorption-devices-for-treating-respiratory-failure-in-people-with-covid19-pdf-2285965456587205. Accessed 2020 Jun 8.
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- Terumo BCT and Marker Therapeutics received the first device FDA Emergency Use Authorization (EUA) to treat acute respiratory failure in COVID-19 patients. Vaughan (ON): Terumo Medical Canada; 2020 Apr 10: https://www.terumocanada.ca/content/terumo-tmci-www/en_ca/home/news-and-event-list/news/terumo-bct-marker-therapeutics-receive-first-fda-eua.html. Accessed 2020 Jun 2.
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