REVIEW ARTICLE


https://doi.org/10.5005/jp-journals-10089-0019
Journal of Acute Care
Volume 1 | Issue 2 | Year 2022

Hemoadsorption (CytoSorb®) in Management of Cytokine Storm and Implication in COVID-19 Pandemic


Harish M Maheshwarappa1https://orcid.org/0000-0001-9377-3421, Shreedhar S Joshi2, Robert James Premkumar3, Shivangi Mishra4https://orcid.org/0000-0003-4960-2400, Shiva Prasad5

1,3,4Department of Critical Care Medicine, Mazumdar Shaw Medical Centre, Narayana Health, Bengaluru, Karnataka, India

2Department of Cardiac Anesthesia, Narayana Health, Bengaluru, Karnataka, India

5Department of Internal Medicine, Narayana Health, Bengaluru, Karnataka, India

Corresponding Author: Harish M Maheshwarappa, Department of Critical Care Medicine, Mazumdar Shaw Medical Centre, Narayana Health, Bengaluru, Karnataka, India, Phone: +91 8095218493, e-mail: mmharish011@gmail.com

Received on: 08 September 2022; Accepted on: 13 September 2022; Published on: 31 December 2022

ABSTRACT

Introduction: Sepsis-related deaths contribute up to 20% of all global deaths, with the highest-burden from sub-Saharan Africa and Southeast Asia. Cytokines are the mediators of organ dysfunction in systemic inflammatory response syndrome (SIRS) across varied etiologies, including sepsis. The imbalance of pro-and anti-inflammatory cytokines continues to be the crux of the pathophysiology of organ dysfunction in septic shock. Therapies to treat cytokines either by antagonizing them or filtering them out of the body are evolving. Hemoadsorption is a process of filtering out cytokines and other metabolites involved in SIRS by surface adsorption.

Materials and methods: We searched for terms–Hemoadsorption, CytoSorb, in PubMed and Google Scholar. We enrolled manuscripts with patients at Indian Centers for review. We extend our review of cytokine storm in COVID-19 and the utility of CytoSorb as an adjuvant in the management of septic shock in COVID-19.

Conclusion: Severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2) infection causing COVID-19 (Coronavirus disease - 2019) pandemic has affirmed cytokine storm as the principal pathology causing morbidity and mortality. Management strategies are mostly supportive since specific antiviral therapy is still in the incipient stage. Cytokine adsorption is being used across most Western countries in COVID-19 septic shock. COVID-19 with cytokine storm as its main pathology is a suitable substrate for the use of CytoSorb. COVID-19 patients with elevated cytokine levels can be offered CytoSorb® hemoadsorption along with other supportive therapies.

How to cite this article: Maheshwarappa HM, Joshi SS, Premkumar RJ, et al. Hemoadsorption (CytoSorb®) in Management of Cytokine Storm and Implication in COVID-19 Pandemic. J Acute Care 2022;1(2):61-67.

Source of support: Nil

Conflict of interest: None

Keywords: Blood filtration, Coronavirus disease 2019, Cytokine storm, CytoSorb®, Hemoadsorption.

INTRODUCTION

An estimated 48.9 million incident cases of sepsis were registered in 2017, with sepsis accounting for 19.7% of all global deaths. India contributed 11.3 million of these sepsis cases in 2017. Sepsis-related age-standardized incidence is 992/100,000 population.1 The mortality rate with severe sepsis is about 30% in the Indian population. With low and mid-socioeconomic countries contributing to the doubling of sepsis globally in the last decade, a need for early diagnosis and treatment needs no emphasis. Newer insights into the pathophysiology of sepsis revolve around the imbalance in inflammatory mediators.2 Cytokines act as mediators that are pivotal in the pathophysiology of sepsis.3 Therapy to reduce, block, and filter cytokines continue to lure intensive care physicians around the globe. The present SARS-CoV-2 infection has generated interest for cytokine therapies in its management.4

MATERIALS AND METHODS

We performed a literature review on the use of cytokine hemoadsorption therapies in Indian patients and looked at the clinical implications of such therapies in the current COVID-19 pandemic. An extensive literature search was done for keywords “hemoadsorption” and “CytoSorb®” using PubMed and Google Scholar search engines. All manuscripts with patients at Indian centers enrolled. We extend our review of cytokine storm in COVID-19 and the utility of CytoSorb® as an adjuvant in the management of septic shock in COVID-19.

Cytokine Storm

Cytokines are a varied group of proteins released by our immune system and play an essential role in normal immune responses. There are different cytokines, including chemokines, interferons, interleukins (IL), lymphokines, and tumor necrosis factor (TNF). The primary functions of cytokines include inflammatory response, angiogenesis, down and upregulation of receptors, and control of cell differentiation.5

However, in response to a severe immune reaction, many cytokines are released into the bloodstream. This sudden increase in cytokines is known as a cytokine storm.5 It can be severe or life-threatening and lead to multiple organ failures. Secondary hemophagocytic lymphocytic histiocytosis (sHLH), commonly triggered by viral infections (seen in 3.7–4.3% of sepsis patients), is a hyperinflammatory syndrome associated with fulminant cytokinemia with multiorgan failure.6-8 It is accompanied by unremitting fever, cytopenia, and hyperferritinemia; pulmonary involvement in the form of acute respiratory distress syndrome (ARDS) occurs in up to 50% of patients with sHLH.12 In patients with COVID-19, a cytokine storm resembling sHLH with a predominance of IL-2, IL-7, granulocyte stimulating factor, and TNFα has been observed.9-12

Extracorporeal (EC) Therapies for the Management of Cytokine Storm

Pharmacologic and blood purification techniques (BPT) are the two primary techniques used for cytokine removal. Pharmacological therapies include monoclonal antibodies [e.g., human monoclonal immunoglobulin (Ig) M antibody, anti-TNFα], polyclonal anti-lipopolysaccharide antibody, serotonin protease inhibitors, and antioxidant micronutrients. BPT includes hemofiltration, hemoperfusion, intermittent or continuous high-volume hemofiltration, plasmapheresis, or hemoadsorption.9

CytoSorb®: An EC Cytokine Hemoadsorber

CytoSorb® (CytoSorbents Corporation, Monmouth Junction, New Jersey, United States (US) of America) is an advanced hemocompatible, biocompatible, bead-based, and porous polymer technology that confers an adequate binding capacity with a well-established potential to lower a wide range of cytokines. It comprises polyvinylpyrrolidone-coated biocompatible beads of the polymer; polystyrene-divinylbenzene and has highly advanced unique features than the normal hemofilter (Fig. 1). The removal of substances from the whole blood is dependent on surface adsorption and pore capture. Each bead is around the size of a grain of salt and can bind to a wide range of inflammation-inducing mediators like chemokines, cytokines, and toxins (Fig. 2).

Fig. 1: Hemofiltration vs hemoadsorber (Source: adapted presentations with permission of Pradeep Yanamala of Biocon Biologics Limited, Bengaluru, India)

Fig. 2: CytoSorb® adsorber pictorial presentation

CytoSorb® Unique Features

  • High Surface Area

    The purification of blood occurs through adsorption that is similar to hemoperfusion (Fig. 3). The beads have an estimated pore size of 300–800 μm that confers >40,000 m2, whereas the total surface area of membrane filters is around 2 m (half table tennis court). The large surface area provides a more significant potential for clearance than the other available dialyzers.13

  • Broad Spectrum of Adsorption

    CytoSorb® can eliminate hydrophobic molecules like cytokine with a size of around 55 kDa. The removal process is concentration dependent to such an extent that it cannot affect the low cytokine levels (Fig. 4). CytoSorb brings down the elevated plasma levels of mediators, which results in the turning off of abnormal immune response of the body. It results in a proper immune balance and modulation. Other metabolic products like bilirubin, free hemoglobin, and myoglobin can also be expelled from the circulation. Albumin remains unaffected (Fig. 5).

  • Ease of Setup

    CytoSorb® can quickly and easily be integrated into an EC circuit like standard hemodialysis and extracorporeal membrane oxygenation (ECMO). CytoSorb® is compatible with both systemic regional citrate and heparin anticoagulation. The average span of treatment is up to 24 hours for each setting, day by day, for 2–7 consecutive days. Blood flow is typically set in the range of 150–700 mL/minute (Fig. 6).13,15

Fig. 3: CytoSorb® adsorption works on concentration-dependent adsorption. High concentration of substance results in high removal efficiency and low concentration of substance leading to low/no removal efficiency. No complete removal/overtreatment possible of physiological mediators

Fig. 4: CytoSorb® adsorption spectrum

Fig. 5: No removal of coagulation factors and Igs and no complete removal of physiologic mediators

Figs 6A to C: CytoSorb® circuit: (A) As an independent therapy; (B) Before the dialyzer mode; (C) After the dialyzer mode

CytoSorb®: Field of Application

CytoSorb® is an International Organization for Standardization 13485 certified and conformitè europëenne (CE) marking validated EC adsorber of cytokine, which is predominantly designed to reduce cytokine storm. CytoSorb® is also approved in European Union.16 Currently, CytoSorb is used in patients with septic shock and vasoplegic shock in the context of noninfectious triggers (e.g., cardiac surgery patients). Other areas of application that are currently being intensively researched include polytrauma and severe burns, acute pancreatitis, different types of liver failure, and severe cardiogenic shock.17-19 On 10th April 2020, the US Food and Drug Administration (FDA) issued emergency use authorization (EUA) to CytoSorb® to treat confirmed COVID-19 patients. Patients should be 18-year-old or more and must have been admitted to the intensive care unit (ICU) with confirmed or approaching failure of respiration. Indian Health Authority also approved the use of CytoSorb® in case of elevated levels of cytokines and to treat patients (18 years and older) with confirmed COVID-19.

Selecting the right patient: below mentioned parameters may be considered for selecting the right patient:

  • A patient who is not able to be stabilized clinically with medical treatment.

  • Onset of shock in the last 24 hours.

  • Positive fluid balance that shows a capillary leak and resistance to diuretic therapy.

  • One or more organ dysfunction—acute lung injury/ARDS/acute kidney injury (AKI)/hepatic dysfunction.

  • Up-trending systemic inflammatory markers [procalcitonin (PCT)/IL-6].

Starting the therapy at the right time: recent trials indicate better clinical outcomes if the therapy is initiated within 24 hours of clinical diagnosis of sepsis.20,21

A CytoSorb® scoring system was proposed (Fig. 7) based on established and clinical parameters that help to identify the patients with early refractory septic shock who would benefit most from CytoSorb® therapy. Scores in the range 8–13 are considered ideal for recommending CytoSorb therapy. Scores >13 implies that the patient’s condition is critical and requires aggressive therapy.22,23

Fig. 7: CytoSorb® checklist scorecard

Though the optimal length of the therapy is still being evaluated, early reports of use for 6 hours every 24 hours over 7 days are flawed by the conceptual hypothesis of cytokine gradient across the tissue.24 No discrete evidence exists on the duration of therapy because of the inconsistent monitoring guide. Blood cytokine levels or PCT have not been consistent, and hence their clearance cannot be routinely used to time the initiation and ending of therapy.25,26

When should the therapy be weaned off?

  • If the systemic hyper inflammation is found to be under control (tapering dose of vasoactive/inotrope therapy, fluid balance reversal, and a notable reduction in edema and lactate level normalization).

  • Improvement in the function of impaired organs (improving oxygenation, improving urine output, and hepatic derangement recovery).

When expected stabilization is not achieved or hemodynamic instability continues, consider starting the second adsorber and reevaluate the patient’s condition after 12–24 hours. If the patient is in refractory shock and does not show any response, consider terminating the therapy, and looking at other supportive therapy.

Review of Indian Literature on CytoSorb®

In a retrospective study in a septic shock patient cohort of 100, Mehta et al. observed the utility of CytoSorb® score as an indication to initiate CytoSorb® therapy.26 Cytokine levels (IL-6, IL-10, and TNF), biomarkers of inflammation [C-reactive protein (CRP) and PCT], and clinical parameters of vasopressor use were observed as endpoints. Of the 100 patients enrolled over 2 years, mortality was observed in 60% of patients. The patients had a better outcome when CytoSorb® therapy was initiated in <48 hours after the onset of septic shock with a reduction in vasopressor use, blood urea nitrogen, serum creatinine, PCT and serum lactate levels, and improved partial pressure of oxygen (PO2) in the arterial blood/fraction of inspired oxygen (FiO2) ratio, urine output, and reduced FiO2 levels. The authors observed the safety profile of CytoSorb® in patients with septic shock and suggested the importance of early initiation of therapy, with 70% of patients surviving when therapy was initiated <48 hours. In a mixed intensive care cohort of postsurgical patients and medical intensive care patients, Singh et al. suggested a safe use of CytoSorb therapy in patients with septic shock. Reduction of PCT levels and sequential organ failure assessment (SOFA) score in survivors was observed. In 48% of survivors, there was a significant reduction in mechanical ventilation time, ICU stays, and overall hospital stays compared to the nonsurvivors.27 A single-center experience using CytoSorb for sepsis and multiple organ dysfunction syndrome (MODS) was reported in a mixed cohort of septic patients. Patients were enrolled over 2 years if they fulfilled the criteria of high vasopressor dose (norepinephrine > 0.3 and dopamine > 15 μg/kg/minute). A total of 75% of the eight cases survived with significant improvement in lactate levels, total leukocyte levels (TLC), and mean arterial pressure (MAP).28 A multicenter prospective use of CytoSorb® in treating septic shock patients along with standard care was conducted in four tertiary care ICUs in India with contributions from our center. Among the 62% of survival patients, 71% received CytoSorb® in <48 hours from the onset of septic shock. Among the nonsurvivors (19 of 45 enrolled patients), there was a reduction in acute physiology and chronic health evaluation (APACHE) score, but higher vasopressor requirements ensued. All patients demonstrated a reduction in pro-inflammatory marker IL-6 after the CytoSorb application.29

Our Experience with CytoSorb®

In our experience with using CytoSorb® for 45 patients with sepsis and sepsis shock, as part of a multicenter observational study, 26 patients survived. The primary outcome was MAP improvement and vasopressor requirement, while the secondary outcome was a change in the laboratory and vital parameters and sepsis scores. Amongst the survivors, the decrease in the requirement of noradrenaline, adrenaline, and vasopressin was 51.4, 69.4, and 13.0%, respectively. The reduction in IL-6, TLC, serum creatinine, and lactate was 52.3, 33, 33.3, and 39.4%, respectively. The platelet count improved by 30.1%. There was a significant improvement in the APACHE II scores (25.46 ± 2.91−20.1 ± 2.47; p < 0.0001) and SOFA scores (12.90 ± 4.02−9.04 ± 3.00; p = 0.0003). The actual mortality was 48.8% compared to the predicted mortality of 56.5%. The number of ICU days was 4.44 ± 1.66 days in the survivors compared to 8.5 ± 15.9 days in the nonsurvivors. Therefore, we concluded that CytoSorb® could be an effective adjuvant therapy in managing patients with sepsis and septic shock.

Regain Control of Critically Ill COVID-19 Patients

As seen in influenza, other coronavirus infections (e.g., SARS and Middle East respiratory syndrome), and now COVID-19 infection develop a cytokine storm, driving systemic hyper inflammation with capillary leak syndrome, organ injury, and other complications.30 In critically ill patients in the ICU, this contributes to a high risk of death due to a high incidence of complications such as ARDS (61%), shock (31%), AKI (8%), acute cardiac injury (22%) and arrhythmias (44%), and other organ dysfunction.31 Ruan et al. observed a significantly higher IL-6, CRP, and ferritin levels in COVID-19 patients with mortality (CRP; 126.6 vs 34.1 μg/L, p < 0.001, ferritin; 1,297.6 vs 614 μg/mL control, p < 0.001).32

Though not definitive, the cytokine and inflammatory marker profile associated with COVID-19 disease severity resemble sHLH, a severe hyperinflammatory syndrome.33 Overall, cytokine storm seems to be a fundamental problem in some critically ill COVID-19 patients, and controlling the inflammatory response may be as important as targeting the virus.32,33

Coronavirus Disease 2019 and CytoSorb®

The exaggerated early response of the neutrophils and pro-inflammatory cytokine responses (TNFα, IL-6, and IL-1β) is the most evolving hypothesis in COVID-19 too.34 Another published study stated the use of new extracorporeal (EC) organ support therapies, including hemoadsorption and hemoperfusion, to manage sepsis patients with COVID-19.35 Expert recommendations on blood purification strategies in managing COVID-19 suggest cytokine filtration as adjuvant therapy. In its interim decision, US FDA authorized CytoSorb by giving the EUA to treat patients more than 18-year-old with a confirmed diagnosis of COVID-19 in ICU with imminent respiratory failure to reduce pro-inflammatory cytokine levels.36,37 Currently, critically ill patients with COVID-19 are being enrolled to study the effects of cytokine filtration with CytoSorb (CYTOCOV-19). The rise of ECMO as a supportive modality in the COVID-19 pandemic is already evident.38,39

Experience in Treatment of Patients with COVID-19 Infection

More than 750 critically ill patients with COVID-19 are treated with CytoSorb® in different centers of the countries, namely Italy, Germany, and China. Though the data of patients are not entirely available owing to the vulnerable circumstances in the countries mentioned above, the promising results in Italy have led the “Italy Brescia Renal COVID Task Force” and the “European Renal Association-European Dialysis and Transplant Association,” to recommend the use of CytoSorb® in patients with COVID-19 who are severely ill and are in stage III AKI going through the continuous renal replacement therapy.40 Additionally, the contemporary National guidelines in Panama on adult COVID-19 patients have also recommended CytoSorb® therapy.41

Clinical Criteria for the Use of CytoSorb® Therapy in Critically Ill Patients with COVID-19

Plasma adsorption solely or in association with plasma exchange/filtration in the artificial Liver support system is indicated for increasing inflammatory mediators (IL-6 >5 upper limit of normal or rising >1 time/day) and pulmonary pathology >10% progression/day.42 In an expert recommendation consensus, blood purification in severe COVID-19 disease should be offered for patients with renal dysfunction (stage >2 AKI kidney disease improving global outcomes, severe fluid overload causing electrolyte disturbances), severe ARDS with septic shock, and raising IL-6 levels >5 times normal. BPT intended to filter inflammatory mediators are suggested as soon as possible, with rising cytokine levels to >5 times normal or >1 time increase/day. Weaning is considered to improve pulmonary function (improving PO2:FiO2 ratio, resolving infiltrations, and improving lung compliance), correcting liver dysfunction, and IL-6 dropping to <2 times normal values.36 In the absence of indication or nonavailability of tocilizumab, COVID-19 in patients on dialysis or renal transplant recipients, CytoSorb is recommended for 24–48 hours by the Italy Brescia Renal COVID Taskforce.40 The National guidelines of Panama for adult COVID-19 management suggest the following criteria as an indication for CytoSorb®—Profound vasoplegia with elevated lactate levels and high need for vasopressors (e.g., NE >0.3 μg/kg/minute) not responding to standard therapy; severe ARDS requiring high ventilatory support; and adjuvant to ECMO/EC life support therapy.

CONCLUSION

Cytokine storm is a predominant mediator in multiorgan dysfunction in SIRS with varied etiologies. Hemoadsorption of cytokines with CytoSorb® has widespread clinical utility beyond septic shock in Indian literature. In the present COVID-19 pandemic, the pathophysiology of MODS revolves around cytokine storm, and CytoSorb® is being used with variable success. In view of the FDA/EUA approval of CytoSorb® for COVID-19 shock, it can be offered as supportive therapy for COVID-19 septic shock.

AUTHOR CONTRIBUTION

All authors have contributed to the concept, design of the study, acquisition of data, and drafting and revising of the article. The authors agree to be responsible for all aspects of the work.

ORCID

Harish M Maheshwarappa https://orcid.org/0000-0001-9377-3421

Shivangi Mishra https://orcid.org/0000-0003-4960-2400

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