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Blood purification could tackle COVID-19?

Abstract

Coronavirus disease 2019 (COVID-19) threatened human lives worldwide since first reported. The current challenge for global intensivists is to establish an effective treatment for severe COVID-19. Blood purification has been applied to the treatment of various critical illnesses. Theoretically, its technique also has an enormous possibility of treating severe COVID-19 in managing inflammatory cytokines and coagulopathy. Recent clinical studies have revealed the positive clinical effect of therapeutic plasma exchange. Other studies have also indicated the considerable potential of other blood purification techniques, such as Cytosorb, AN69 surface-treated membrane, and polymyxin b hemoperfusion. Further research is needed to elucidate the actual effects of these applications.

Background

Coronavirus disease 2019 (COVID-19) has been a new threat to humans since it was first reported in Wuhan, China. Despite the development of vaccines and medical treatment, a portion of COVID-19 patients become critically ill due to acute respiratory distress syndrome (ARDS) and other complications [1,2,3,4]. As recent basic studies indicate, these multiorgan dysfunctions mainly derive from three pathogeneses: cytokine storm, excessive inflammatory response, and hypercoagulation [5, 6]. To tackle this global crisis, we need to establish a treatment to control these pathological mechanisms.

Blood purification is a type of therapy based on the extracorporeal treatment of blood [7]. It has been widely used to treat severe refractory disorders to conventional therapies, such as fulminant liver failure, collagen diseases, and transplant rejection [8]. These applications have theoretical backgrounds such as suppressing excessive inflammation, lessening the cytokine storm, and correcting the coagulopathy. Many physicians are now wondering if this theoretical application could also be favorable in the treatment of patients with severe COVID-19. Based on this background, we focus on the positive possibility of blood purification in COVID-19.

Main text

Therapeutic plasma exchange

Therapeutic plasma exchange (TPE) is a blood purification therapy that efficiently separates the plasma from the blood cells and replaces it with fresh frozen plasma. Theoretically, the technique could both remove the pathological plasma with multiple cytokines and normalize the coagulopathy. Since the beginning of the COVID-19 pandemic, there have been case reports of the successful TPE treatment of patients with severe COVID-19 [9,10,11,12].These reports also demonstrated improved cytokine concentrations and coagulation markers immediately after the TPE procedure [10,11,12]. Clinical studies were also initiated to examine the clinical effect of TPE on severe COVID-19 cases (Table 1).

Table 1 Summary of the published studies investigating the effect of therapeutic plasma exchange for COVID-19

Using a retrospective propensity score-matched analysis, Gucyetmez et al. compared the prognosis of COVID-19 patients in the intensive care unit (ICU) between patients receiving standard therapy alone and patients receiving standard therapy plus TPE [13]. As in previous reports, this study showed that TPE decreased interleukin-6 (IL-6) and D-dimer levels. Additionally, among patients with higher D-dimer (2) levels, the TPE group had a significantly lower mortality rate (8% vs. 58%; p < 0.01). Kamran et al. also applied a similar analysis to 280 COVID-19 patients and investigated the clinical effect of TPE [14]. They found that the TPE group’s 28-day survival rate was significantly superior (91% vs. 62%; p < 0.01). The median duration of hospitalization was also reduced in the TPE group (10 days vs. 15 days; p < 0.01). These retrospective studies suggested that TPE could improve the laboratory markers and ameliorate the prognosis of severe COVID-19 cases [13,14,15].

To address the same clinical question, Faqihi et al. designed a randomized controlled trial (RCT) that compared standard therapy alone with standard therapy plus TPE [16]. Although the 35-day mortality rate was not significantly lower in the TPE group (21% vs. 34%, p = 0.09), the duration of mechanical ventilation (15 days vs. 19 days; p < 0.01) and ICU stay (19 days vs. 26 days; p = 0.02) was significantly reduced. This RCT’s results also supported the efficacy of TPE for severe COVID-19 cases.

Cytosorb

Cytosorb is a hemadsorption device that was approved in the European Union in 2011 for cytokine adsorption [17]. Its therapeutic impact on cytokine removal has been reported in various critical diseases, such as septic shock and cardiac surgery [18, 19]. One feature of this device is that it permits combination with other extracorporeal blood treatments, including continuous kidney replacement therapy (CKRT) and extracorporeal membrane oxygenation (ECMO). The co-treatment efficacy of Cytosorb and venous–venous ECMO (V–V ECMO) for severe COVID-19 pneumonia has been investigated in several clinical studies [20,21,22].

Rieder et al. preliminarily revealed that the initiation of V–V ECMO with Cytosorb markedly decreased the IL-6 level of COVID-19 patients [23]. They performed an open-label, multicenter RCT to evaluate the effect of V–V ECMO and Cytosorb for severe COVID-19-related ARDS [24]. In contrast to their preliminary data, however, their RCT’s results countered the authors’ expectations [25]. Namely, the 30-day survival rate was considerably lower in the Cytosorb group (18% vs. 76%; p < 0.01). Even the serum IL-6 level after 72 h was not significantly reduced (99 pg/mL vs. 112 pg/mL; p = 0.54). As such, they concluded that early Cytosorb initiation should be avoided in severe COVID-19 patients requiring V–V ECMO.

It is of note, however, that this RCT’s results have been questioned in regard to randomization, timing of ECMO, and serum IL-6 concentrations [26, 27]. Therefore, it might be premature to rush to negative conclusions about the efficacy of Cytosorb. There are other RCTs that are currently examining the effects, such as NCT04518969, NCT04344080, DRKS00021447, and further investigations are expected [28].

Modified AN69ST (Oxiris) and polymyxin b hemoperfusion

Oxiris is a newly developed CKRT hemofilter with an AN69 surface-treated membrane [29]. It provides high absorbance of endotoxin (negatively charged) and excellent anti-thrombogenicity because of its positively charged polyethyleneimine coating and heparin grafting [30]. Several case series and studies have already reported the hemofilter’s validity in reducing cytokine concentrations in COVID-19 patients [31,32,33,34,35].

Polymyxin b hemoperfusion (PMX-DHP) is another widely used blood purification therapy for septic shock patients [36]. The hemoperfusion therapy removes circulating endotoxins through the adsorption to polymyxin b-immobilized columns. Although the treatment efficacy was not supported by recent guidelines, some case series have shown the clinical value of PMX-DHP for COVID-19 patients [37,38,39,40]. Other studies also revealed that PMX-DHP could decrease levels of IL-6 and other inflammatory chemokines [41].

Unfortunately, the efficacy of these two therapies has not yet been sufficiently examined with control studies or RCTs. In vitro examinations indicate that these techniques could calm cytokine storms, however, and future research is thus warranted.

Conclusions

Blood purification has excellent potential to fight the COVID-19 pandemic. TPE, in particular, could be helpful in the clinical management of cytokine storms and coagulopathy. The efficacy of other techniques has also been supported by several clinical and in vitro studies. Further research is needed to elucidate the actual effects of these applications.

Availability of data and materials

All descriptions are based on the published data.

Abbreviations

ARDS:

Acute respiratory distress syndrome

CKRT:

Continuous kidney replacement therapy

COVID-19:

Coronavirus disease 2019

ECMO:

Extracorporeal membrane oxygenation

ICU:

Intensive care unit

PMX-DHP:

Polymyxin b hemoperfusion

RCT:

Randomized controlled trial

TPE:

Therapeutic plasma exchange

References

  1. 1.

    COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. https://www.covid19treatmentguidelines.nih.gov/. Accessed 20 Sep 2021.

  2. 2.

    Bhimraj A MR, Shumaker AH, Lavergne V, Baden L, Cheng VC, Edwards KM, Gandhi R, Gallagher J, Muller WJ, O'Horo JC, Shoham S, Murad MH, Mustafa RA, Sultan S, Falck-Ytter Y. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. Infectious Diseases Society of America 2021; Version 5.2.0. https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/. Accessed 20 Sep 2021.

  3. 3.

    Alhazzani W, Evans L, Alshamsi F, Møller MH, Ostermann M, Prescott HC, Arabi YM, Loeb M, Ng Gong M, Fan E, et al. Surviving sepsis campaign guidelines on the management of adults with coronavirus disease 2019 (COVID-19) in the ICU: first update. Crit Care Med. 2021. https://doi.org/10.1097/CCM.0000000000004899.

    Article  PubMed  Google Scholar 

  4. 4.

    Yamakawa K, Yamamoto R, Ishimaru G, Hashimoto H, Terayama T, Hara Y, Hasegawa D, Ishihara T, Imura H, Okano H, et al. Japanese Rapid/Living recommendations on drug management for COVID-19. Acute Med Surg. 2021;8(1): e664.

    PubMed Central  Google Scholar 

  5. 5.

    Harrison AG, Lin T, Wang P. Mechanisms of SARS-CoV-2 transmission and pathogenesis. Trends Immunol. 2020;41(12):1100–15.

    Article  CAS  Google Scholar 

  6. 6.

    Sun J, He WT, Wang L, Lai A, Ji X, Zhai X, Li G, Suchard MA, Tian J, Zhou J, et al. COVID-19: epidemiology, evolution, and cross-disciplinary perspectives. Trends Mol Med. 2020;26(5):483–95.

    Article  CAS  Google Scholar 

  7. 7.

    Ren J, Wei HL, Xu L, Jia LY. 5.55—Blood detoxication. In: Burlington M-YM, editor. Comprehensive biotechnology (second edition). Academic Press: Cambridge; 2011. p. 729–39.

    Chapter  Google Scholar 

  8. 8.

    Padmanabhan A, Connelly-Smith L, Aqui N, Balogun RA, Klingel R, Meyer E, Pham HP, Schneiderman J, Witt V, Wu Y, et al. 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. J Clin Apher. 2019;34(3):171–354.

    Article  Google Scholar 

  9. 9.

    Keith P, Day M, Choe C, Perkins L, Moyer L, Hays E, French M, Hewitt K, Gravel G, Guffey A, et al. The successful use of therapeutic plasma exchange for severe COVID-19 acute respiratory distress syndrome with multiple organ failure. SAGE Open Med Case Rep. 2020;8: 2050313x20933473.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Zhang L, Zhai H, Ma S, Chen J, Gao Y. Efficacy of therapeutic plasma exchange in severe COVID-19 patients. Br J Haematol. 2020;190(4):e181–3.

    Article  CAS  Google Scholar 

  11. 11.

    Morath C, Weigand MA, Zeier M, Speer C, Tiwari-Heckler S, Merle U. Plasma exchange in critically ill COVID-19 patients. Crit Care. 2020;24(1):481.

    Article  Google Scholar 

  12. 12.

    Liu J, Dong YQ, Yin J, He G, Wu X, Li J, Qiu Y, He X. Critically ill patients with COVID-19 with ECMO and artificial liver plasma exchange: a retrospective study. Medcine (Baltimore). 2020;99(26): e21012.

    Article  CAS  Google Scholar 

  13. 13.

    Gucyetmez B, Atalan HK, Sertdemir I, Cakir U, Telci L. Therapeutic plasma exchange in patients with COVID-19 pneumonia in intensive care unit: a retrospective study. Crit Care. 2020;24(1):492.

    Article  Google Scholar 

  14. 14.

    Kamran SM, Mirza ZE, Naseem A, Liaqat J, Fazal I, Alamgir W, Saeed F, Saleem S, Nisar S, Yousaf MA, et al. Therapeutic plasma exchange for coronavirus disease-2019 triggered cytokine release syndrome; a retrospective propensity matched control study. PLoS ONE. 2021;16(1): e0244853.

    Article  CAS  Google Scholar 

  15. 15.

    Khamis F, Al-Zakwani I, Al Hashmi S, Al Dowaiki S, Al Bahrani M, Pandak N, Al Khalili H, Memish Z. Therapeutic plasma exchange in adults with severe COVID-19 infection. Int J Infect Dis. 2020;99:214–8.

    Article  CAS  Google Scholar 

  16. 16.

    Faqihi F, Alharthy A, Abdulaziz S, Balhamar A, Alomari A, AlAseri Z, Tamim H, Alqahtani SA, Kutsogiannis DJ, Brindley PG, et al. Therapeutic plasma exchange in patients with life-threatening COVID-19: a randomised controlled clinical trial. Int J Antimicrob Agents. 2021;57(5): 106334.

    Article  CAS  Google Scholar 

  17. 17.

    Ankawi G, Xie Y, Yang B, Xie Y, Xie P, Ronco C. What have we learned about the use of cytosorb adsorption columns? Blood Purif. 2019;48(3):196–202.

    Article  CAS  Google Scholar 

  18. 18.

    Hawchar F, László I, Öveges N, Trásy D, Ondrik Z, Molnar Z. Extracorporeal cytokine adsorption in septic shock: a proof of concept randomized, controlled pilot study. J Crit Care. 2019;49:172–8.

    Article  CAS  Google Scholar 

  19. 19.

    Poli EC, Alberio L, Bauer-Doerries A, Marcucci C, Roumy A, Kirsch M, De Stefano E, Liaudet L, Schneider AG. Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial. Crit Care. 2019;23(1):108.

    Article  Google Scholar 

  20. 20.

    Alharthy A, Faqihi F, Memish ZA, Balhamar A, Nasim N, Shahzad A, Tamim H, Alqahtani SA, Brindley PG, Karakitsos D. Continuous renal replacement therapy with the addition of CytoSorb cartridge in critically ill patients with COVID-19 plus acute kidney injury: a case-series. Artif Organs. 2021;45(5):E101-e112.

    Article  CAS  Google Scholar 

  21. 21.

    Nassiri AA, Hakemi MS, Miri MM, Shahrami R, Koomleh AA, Sabaghian T. Blood purification with CytoSorb in critically ill COVID-19 patients: a case series of 26 patients. Artif Organs. 2021. https://doi.org/10.1111/aor.14024.

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Wunderlich-Sperl F, Kautzky S, Pickem C, Hörmann C. Adjuvant hemoadsorption therapy in patients with severe COVID-19 and related organ failure requiring CRRT or ECMO therapy: a case series. Int J Artif Organs. 2021;44: 3913988211030517.

    Article  CAS  Google Scholar 

  23. 23.

    Rieder M, Wengenmayer T, Staudacher D, Duerschmied D, Supady A. Cytokine adsorption in patients with severe COVID-19 pneumonia requiring extracorporeal membrane oxygenation. Crit Care. 2020;24(1):435.

    Article  Google Scholar 

  24. 24.

    Rieder M, Schubach F, Schmoor C, von Spee-Mayer C, Wengenmayer T, Rilinger J, Staudacher D, Bode C, Duerschmied D, Supady A. Cytokine adsorption in patients with severe COVID-19 pneumonia requiring extracorporeal membrane oxygenation: protocol for a randomised, controlled, open-label intervention, multicentre trial. BMJ Open. 2021;11(1): e043345.

    Article  Google Scholar 

  25. 25.

    Supady A, Weber E, Rieder M, Lother A, Niklaus T, Zahn T, Frech F, Müller S, Kuhl M, Benk C, et al. Cytokine adsorption in patients with severe COVID-19 pneumonia requiring extracorporeal membrane oxygenation (CYCOV): a single centre, open-label, randomised, controlled trial. Lancet Respir Med. 2021;9(7):755–62.

    Article  CAS  Google Scholar 

  26. 26.

    Rybalko A, Voronin AV, Karpun NA. Cytokine adsorption and ECMO in patients with COVID-19. Lancet Respir Med. 2021;9(8):e69–70.

    Article  CAS  Google Scholar 

  27. 27.

    Nardelli P, Pieri M, Fominskiy E, Scandroglio AM. Cytokine adsorption and ECMO in patients with COVID-19. Lancet Respir Med. 2021;9(8):e71–e71.

    Article  CAS  Google Scholar 

  28. 28.

    Stockmann H, Keller T, Büttner S, Jörres A, Kindgen-Milles D, Kunz JV, Leebmann J, Spies C, Träger K, Treskatsch S, et al. 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. Trials. 2020;21(1):577.

    Article  CAS  Google Scholar 

  29. 29.

    Hattori N, Oda S. Cytokine-adsorbing hemofilter: old but new modality for septic acute kidney injury. Renal Replacement Therapy. 2016;2(1):41.

    Article  Google Scholar 

  30. 30.

    Schwindenhammer V, Girardot T, Chaulier K, Grégoire A, Monard C, Huriaux L, Illinger J, Leray V, Uberti T, Crozon-Clauzel J, et al. oXiris® use in septic shock: experience of two French centres. Blood Purif. 2019;47:29–35.

    Article  Google Scholar 

  31. 31.

    Zhang H, Zhu G, Yan L, Lu Y, Fang Q, Shao F. The absorbing filter Oxiris in severe coronavirus disease 2019 patients: a case series. Artif Organs. 2020;44(12):1296–302.

    Article  CAS  Google Scholar 

  32. 32.

    Peerapornratana S, Sirivongrangson P, Tungsanga S, Tiankanon K, Kulvichit W, Putcharoen O, Kellum JA, Srisawat N. Endotoxin adsorbent therapy in severe COVID-19 pneumonia. Blood Purif. 2021. https://doi.org/10.1159/000515628.

    Article  PubMed  Google Scholar 

  33. 33.

    Ugurov P, Popevski D, Gramosli T, Neziri D, Vuckova D, Gjorgon M, Stoicovski E, Marinkovic S, Veljanovska-Kiridjievska L, Ignevska K, et al. Early initiation of extracorporeal blood purification using the AN69ST (oXiris®) hemofilter as a treatment modality for COVID-19 patients: a single-centre case series. Braz J Cardiovasc Surg. 2020. https://doi.org/10.21470/1678-9741-2020-0403.

    Article  PubMed  Google Scholar 

  34. 34.

    Rosalia RA, Ugurov P, Neziri D, Despotovska S, Kostoska E, Veljanovska-Kiridjievska L, Kuzmanov D, Trifunovski A, Popevski D, Villa G, et al. Extracorporeal blood purification in moderate and severe COVID-19 patients: a prospective cohort study. Blood Purif. 2021. https://doi.org/10.1159/000515627.

    Article  PubMed  Google Scholar 

  35. 35.

    Villa G, Romagnoli S, De Rosa S, Greco M, Resta M, Pomarè Montin D, Prato F, Patera F, Ferrari F, Rotondo G, et al. Blood purification therapy with a hemodiafilter featuring enhanced adsorptive properties for cytokine removal in patients presenting COVID-19: a pilot study. Crit Care. 2020;24(1):605.

    Article  Google Scholar 

  36. 36.

    Shimizu T, Miyake T, Kitamura N, Tani M, Endo Y. Endotoxin adsorption: direct hemoperfusion with the polymyxin B-immobilized fiber column (PMX). Transfus Apher Sci. 2017;56(5):682–8.

    Article  Google Scholar 

  37. 37.

    Egi M, Ogura H, Yatabe T, Atagi K, Inoue S, Iba T, Kakihana Y, Kawasaki T, Kushimoto S, Kuroda Y, et al. The Japanese clinical practice guidelines for management of sepsis and septic shock 2020 (J-SSCG 2020). J Intensive Care. 2021;9(1):53.

    Article  Google Scholar 

  38. 38.

    Kuwana T, Kinoshita K, Hirabayashi M, Ihara S, Sawada N, Mutoh T, Yamaguchi J. PMX-DHP therapy for dyspnea and deoxygenation in severe COVID-19 pneumonia: a case series. Infect Drug Resist. 2021;14:1305–10.

    Article  Google Scholar 

  39. 39.

    Ishiwari M, Togashi Y, Takoi H, Kikuchi R, Kono Y, Abe S. Polymyxin B haemoperfusion treatment for respiratory failure and hyperferritinaemia due to COVID-19. Respirol Case Rep. 2020;8(9): e00679.

    Article  Google Scholar 

  40. 40.

    Kusaba Y, Izumi S, Takasaki J, Suzuki M, Katagiri D, Katsuno T, Matsumoto S, Sakamoto K, Hashimoto M, Ohmagari N, et al. Successful recovery from COVID-19-associated acute respiratory failure with polymyxin B-immobilized fiber column-direct hemoperfusion. Intern Med. 2020;59(19):2405–8.

    Article  CAS  Google Scholar 

  41. 41.

    Katagiri D, Ishikane M, Asai Y, Izumi S, Takasaki J, Katsuoka H, Kondo I, Ide S, Nakamura K, Nakamoto T, et al. Direct hemoperfusion using a polymyxin B-immobilized polystyrene column for COVID-19. J Clin Apher. 2021;36(3):313–21.

    Article  Google Scholar 

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HY wrote the manuscript. SO supervised the manuscript. Both the authors read and approved the final manuscript.

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Correspondence to Hiroyuki Yamada.

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The authors declare that they have no competing interests directly relevant to this article. Out of this article, HY, and SO received a grant from Japanese Society for the Promotion of Science KAKENHI: 21K16188 and 21K09045, respectively.

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Yamada, H., Ohtsuru, S. Blood purification could tackle COVID-19?. j intensive care 9, 74 (2021). https://doi.org/10.1186/s40560-021-00586-0

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Keywords

  • Plasmapheresis
  • Plasma exchange
  • Cytosorb
  • Apheresis
  • AN69ST
  • Oxiris
  • PMX-DHP
  • Coronavirus
  • Pandemic
  • Cytokine