Extracorporeal Blood Purification Is Appropriate in Critically Ill Patients with COVID-19 and Multiorgan Failure: CON : Kidney360

Journal Logo

Debates in Nephrology

Extracorporeal Blood Purification Is Appropriate in Critically Ill Patients with COVID-19 and Multiorgan Failure: CON

Kashani, Kianoush1,2; Forni, Lui G.3

Author Information
Kidney360 3(3):p 419-422, March 31, 2022. | DOI: 10.34067/KID.0007382020
  • Open

Introduction

The National Cancer Institute defines a cytokine storm as “a severe immune reaction in which the body releases too many cytokines into the blood too quickly, as a result of an infection, autoimmune condition, or other diseases” (1). In general, a cytokine storm is recognized as a manifestation of some acute conditions or treatments that present with high fever, other constitutional symptoms, and signs, along with inflammatory reactions that may be limited to redness, edema, and pain, or, in the severest forms, multiple organ failure leading to death (1,2). The term cytokine storm was first reported as a consequence of graft versus host syndrome in 1993 (3), but later adopted for manifestations of other diseases, particularly infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (4) and coronavirus disease 2019 (COVID-19) (5). Since the first cases of COVID-19, there has been growing evidence it is associated with increased cytokine levels, which may explain the severity of its manifestations in some, particularly those admitted to intensive care units (5,6). Because the unregulated release of cytokines has been proposed as the primary pathophysiology of this syndrome, it is no surprise that immunomodulation, immunosuppression (7), or a range of extracorporeal cytokine removal techniques have been suggested as potential therapeutic options or trial protocols (8).

To expect any intervention to change the outcomes of any disease, the intervention should target its pathophysiology to enable normal homeostasis or moderate the response to the offending agent or infection. Although extracorporeal cytokine removal techniques for the management of COVID-19 may seem attractive, their effect on important clinical outcomes such as survival is questionable. We discuss why extracorporeal cytokine removal techniques for the management of COVID-19 may not be quite ready (Figure 1A).

F1
Figure 1.:
Issues and solutions to solve the puzzle. (A) Why extracorporeal cytokine removal does not improve clinical outcomes. (B) How extracorporeal cytokine removal could be advanced to augment success.

Reductionist Approach to Modify a Complex System

The definition of a cytokine storm is an ill-defined and predominantly clinical diagnosis with assumptions that the signs and symptoms observed reflect an acute increase in cytokine levels. Cytokines are small proteins excreted by cells (autocrine, paracrine, endocrine) that affect the function of other cells that regulate inflammatory and repair responses. Cytokines are categorized into five groups, including IFNs (antiproliferative, antiviral, and innate immune system regulation), ILs (proinflammatory, leukocyte differentiation), chemokines (proinflammatory, chemotaxis), colony-stimulating factors (stimulation of progenitor cell proliferation and differentiation), and TNFs (proinflammatory, indirect cytotoxicity) (2). Unfortunately, the cytokine physiology complexity and, importantly, the interactions between cytokines in the cytokine storm are poorly understood. The physiology of cytokines is on the basis of the properties of a complex system (9), which include:

  • 1) Nonlinearity: cytokines are intimately interconnected. Many of these proteins have functions related to the other cytokine classes and depend on other cytokine levels, the stage and type of primary illness, and target cells. Besides, although the cytokine system is nonlinear, it is only chaotic in very severe diseases where there is significant dysregulation.
  • 2) Feedback: many feedback loops regulate the cytokine systems. For example, the systemic inflammatory response syndrome (SIRS) is often followed by compensatory anti-inflammatory response syndrome (CARS). Also, the excretion of SIRS- and CARS-related cytokines during sepsis is very dynamic. For example, TNF and IL-1 promote inflammatory cytokines such as IL-6, leading to an increase in anti-inflammatory cytokine release, including IL-10, IL-1 receptor antagonist, and soluble TNF receptor (10). Therefore, if one considers IL-6 removal as a potential therapy, it would only be effective when IL-6 is very elevated and potentially deleterious. Removal during the early response may not be required, and indeed, in the late stages of a cytokine storm may be harmful by influencing the balance between SIRS- and CARS-related cytokines leading to propagation of an inflammatory response.
  • 3) Spontaneous order: the interactions between cytokines are not random. Simultaneously, the order within the cytokine system is not static because multiple factors can affect the role of system components. For instance, genetic variability in toll-like receptor 1 could lead to variability within the innate system in response to gram-positive bacterial infection (11).
  • 4) Although the cytokine system is robust (i.e., self-correction of the errors within the system), it is not centrally controlled. The cytokine system robustness is mainly due to built-in redundancies within the system, which may be disturbed by extracorporeal removal.
  • 5) Emergence: cytokines compete and cooperate (upward and downward causalities) to create a self-organized system with properties that are not specific to individual cytokines.
  • 6) Hierarchical organization: the cytokine system, as any other complex system, includes numerous networks. Within each network, cytokines are self-organized in hierarchies. These networks are also organized hierarchically to maintain or recover the normal homeostasis.
  • 7) Numerosity: there are not only many components within the cytokine system, but also each cytokine participates in several overlapping networks with primary and alternative pathways (12).
  • 8) Many infections have similar cytokine profiles. Yet, they have vastly different modes of action (e.g., SARS-CoV-2 involves pneumocyte type II via angiotensin-converting enzyme 2 receptors, whereas the influenza virus infects ciliated epithelial cells) and clinical manifestations (2).
  • 9) Inflammatory cascades often occur within tissue with a relatively smaller hematogenous proportion. However, most studies focus on circulatory cytokine levels, which may not reflect the conditions within the involved tissue(s) but more a cytokine “dustbin” (2).

Extracorporeal cytokine removal is perceived to have several potential benefits in conditions associated with elevated cytokine levels. These include a decrease in peak cytokine concentrations, thereby mitigating their effects on affected organs, potentially improving outcomes (13). The other suggested benefit is the cytokine response modulation through nonspecific cytokine removal with a potential promotion of appropriate immune cell trafficking to the site of inflammation (13). Although both these hypotheses are valid, they both adopt a somewhat reductionist approach in managing a very complex system, particularly during periods of “cytokine storm.” The dynamic, intricate, and multifunctionality nature of cytokines and the complex interrelations between them may influence nonspecific cytokine removal potential benefits in a nonpredictable fashion. Such a reductionist approach to the cytokine storm complexities may explain why the effect of these techniques on clinical outcomes has not been consistent, despite some observations relaying improved hemodynamics or oxygenation (14).

In a recent consensus conference by the Acute Disease Quality Initiative, the participants suggested inflammatory cytokines and pathogen-associated molecular patterns could contribute to the development of multiple organ failure and mortality in patients with severe COVID-19. Because extracorporeal cytokine removal techniques are shown to remove pathogen-associated molecular patterns and cytokines, they also suggested, despite the lower level of supporting evidence, these techniques to be considered in very carefully selected cases (8). However, in COVID-19, the cytokine storm’s role as a primary pathophysiological mechanism of multiple organ failure is far from convincing. Indeed, in a recent systematic review of 1245 patients with COVID-19, the mean IL-6 level was 100 times less than patients with cytokine release syndrome, 27 times lower than septic patients, and 12 times less than ARDS due to other causes (15).

Solutions and Next Steps

Figure 1, A and B describes the potential reasons that benefits of extracorporeal cytokine removal in patient outcomes have not been consistently observed and provide some of the steps that need to be taken to prepare these techniques to potentially achieve routine adoption. As with any intervention, the efficacy of extracorporeal cytokine removal needs to be assessed in terms of input, intervention, and output. The lack of a verifiable and measurable definition for cytokine storm, the complexity of the cytokine system(s), the dynamic changes observed, the lack of evidence regarding the levels and effect of blood cytokines in COVID-19, and crucially, the lack of readily available routine tests that can measure and monitor cytokine levels in blood and tissues in an accurate and timely fashion make decisions related to both the commencing and continuation of these techniques very challenging. Moreover, most of the available techniques remove cytokines in a nonspecific manner and other potentially important substances, including medications and essential nutrients, to name but two. As a result, consistent information regarding the effect of these techniques on mortality and other hard intensive care unit outcomes has not been regularly reported, and where it has, tends to be in uncontrolled case reports and series or small trials. In our opinion, to demonstrate any benefit from these techniques, several hurdles have to be negotiated. First, cytokine storm needs an objectively measurable definition, which implies we need to measure and monitor cytokine levels regularly. Second, cytokine removal needs to be targeted on the basis of their levels and the potential inter-relationships. To achieve this, additional studies to evaluate tissue and blood cytokine levels together with clinical manifestations of diseases are necessary. Third, new technologies should ideally be enhanced to remove specific cytokines without removing other substances. Fourth, understanding each patient's cytokine landscape using such new monitoring and measurement tools may require harnessing machine learning techniques that may be predictive in highlighting those who may benefit from treatment. Such methods may allow the matching of patients with appropriate personalized treatment plans. Finally, there would be a need for clinical trials to show the assumptions on the basis of the physiology of cytokine removal would translate into patient-level benefits in more meaningful outcomes, including mortality and quality of life and potential financial savings, in terms of consumption of intensive care unit resources.

Disclosures

L.G. Forni reports consultancy agreements with Exther Medical; reports having an ownership interest in Spiden; reports receiving research funding from Baxter; reports receiving honoraria from Astute Medical, Biomerieux, Exthera Medical, Fresenius, and Gambro/Baxter; and reports being a scientific advisor or member as the European Society of Intensive Care Medicine General Secretary. K. Kashani reports consultancy agreements with AM PHARMA; reports receiving research funding from La Jolla Inc.; and reports being scientific advisor or member of General Electric, La Jolla Inc., and MediBeacon Inc.

Funding

None.

See related debate, “Extracorporeal blood purification is appropriate in critically ill patients with COVID-19 and multi-organ failure: PRO,” and commentary, “Extracorporeal blood purification is appropriate in critically ill patients with COVID-19 and multi-organ failure: COMMENTARY,” on pages and , respectively.

Acknowledgments

The content of this article reflects the personal experience and views of the author(s) and should not be considered medical advice or recommendation. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or Kidney360. Responsibility for the information and views expressed herein lies entirely with the author(s).

Author Contributions

K. Kashani conceptualized the study and wrote the original draft; and L.G. Forni reviewed and edited the manuscript.

References

1. Cytokine storm, 2021. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/cytokine-storm. Accessed October 29, 2021
2. Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG: Into the eye of the cytokine storm. Microbiol Mol Biol Rev 76: 16–32, 2012 https://doi.org/10.1128/MMBR.05015-11
3. Ferrara JL, Abhyankar S, Gilliland DG: Cytokine storm of graft-versus-host disease: A critical effector role for interleukin-1. Transplant Proc 25: 1216–1217, 1993
4. Huang KJ, Su IJ, Theron M, Wu YC, Lai SK, Liu CC, Lei HY: An interferon-gamma-related cytokine storm in SARS patients. J Med Virol 75: 185–194, 2005 https://doi.org/10.1002/jmv.20255
5. Cao X: COVID-19: Immunopathology and its implications for therapy. Nat Rev Immunol 20: 269–270, 2020 https://doi.org/10.1038/s41577-020-0308-3
6. Tang Y, Liu J, Zhang D, Xu Z, Ji J, Wen C: Cytokine storm in COVID-19: The current evidence and treatment strategies. Front Immunol 11: 1708, 2020 https://doi.org/10.3389/fimmu.2020.01708
7. Maude SL, Barrett D, Teachey DT, Grupp SA: Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J 20: 119–122, 2014 https://doi.org/10.1097/PPO.0000000000000035
8. Nadim MK, Forni LG, Mehta RL, Connor MJ Jr, Liu KD, Ostermann M, Rimmelé T, Zarbock A, Bell S, Bihorac A, Cantaluppi V, Hoste E, Husain-Syed F, Germain MJ, Goldstein SL, Gupta S, Joannidis M, Kashani K, Koyner JL, Legrand M, Lumlertgul N, Mohan S, Pannu N, Peng Z, Perez-Fernandez XL, Pickkers P, Prowle J, Reis T, Srisawat N, Tolwani A, Vijayan A, Villa G, Yang L, Ronco C, Kellum JA: COVID-19-associated acute kidney injury: Consensus report of the 25th Acute Disease Quality Initiative (ADQI) Workgroup. Nat Rev Nephrol 16: 747–764, 2020 https://doi.org/10.1038/s41581-020-00356-5
9. Ladyman J, Lambert J, Wiesner K: What is a complex system? Euro Jnl Phil Sci 3: 33–67, 2013 https://doi.org/10.1007/s13194-012-0056-8
10. Steeland S, Libert C, Vandenbroucke RE: A new venue of TNF targeting. IJMS 19: 1442, 2018 https://doi.org/10.3390/ijms19051442
11. Wurfel MM, Gordon AC, Holden TD, Radella F, Strout J, Kajikawa O, Ruzinski JT, Rona G, Black RA, Stratton S, Jarvik GP, Hajjar AM, Nickerson DA, Rieder M, Sevransky J, Maloney JP, Moss M, Martin G, Shanholtz C, Garcia JG, Gao L, Brower R, Barnes KC, Walley KR, Russell JA, Martin TR: Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis. Am J Respir Crit Care Med 178: 710–720, 2008 https://doi.org/10.1164/rccm.200803-462OC
12. Anderson PW: More is different. Science 177: 393–396, 1972 https://doi.org/10.1126/science.177.4047.393
13. Peng ZY, Bishop JV, Wen XY, Elder MM, Zhou F, Chuasuwan A, Carter MJ, Devlin JE, Kaynar AM, Singbartl K, Pike F, Parker RS, Clermont G, Federspiel WJ, Kellum JA: Modulation of chemokine gradients by apheresis redirects leukocyte trafficking to different compartments during sepsis, studies in a rat model. Crit Care 18: R141, 2014 https://doi.org/10.1186/cc13969
14. Bonavia A, Groff A, Karamchandani K, Singbartl K: Clinical utility of extracorporeal cytokine hemoadsorption therapy: A literature review. Blood Purif 46: 337–349, 2018 https://doi.org/10.1159/000492379
15. Leisman DE, Ronner L, Pinotti R, Taylor MD, Sinha P, Calfee CS, Hirayama AV, Mastroiani F, Turtle CJ, Harhay MO, Legrand M, Deutschman CS: Cytokine elevation in severe and critical COVID-19: A rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir Med 8: 1233–1244, 2020 https://doi.org/10.1016/S2213-2600(20)30404-5
Keywords:

clinical nephrology; COVID-19; cytokine storm; debates; extracorporeal purification

Copyright © 2022 by the American Society of Nephrology