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Table of Contents
CASE REPORT
Year : 2021  |  Volume : 15  |  Issue : 1  |  Page : 73-75

Immunomodulation in sepsis - A case report


Department of Nephrology, Star Hospitals; Renown Clinical Services, Hyderabad, Telangana, India

Date of Submission10-Apr-2020
Date of Acceptance30-Dec-2020
Date of Web Publication31-Mar-2021

Correspondence Address:
Dr. Rajasekara Chakravarthi Madarasu
Department of Nephrology, Star Hospitals, Road No 10, Banjara Hills, Hyderabad, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_31_20

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  Abstract 


Sepsis and septic shock affect anywhere between 100 and 1000/100,000 person-years and 19 per 100,000 person-years depending on the cohort studied, with mortality rates ranging between 20% and 50%. The recently updated Sepsis 3.0 consensus definitions state that sepsis is an infection accompanied by life-threatening organ dysfunction caused by a dysregulated host response. Given the pivotal role of cytokine production in sepsis and post major surgery, it follows that removal of these substances may attenuate the response particularly in the early phase of sepsis.

Keywords: Cytokine storm, extracorporeal blood purification, immunomodulation, posttransplantation sepsis


How to cite this article:
Madarasu RC, Kumthekar GV. Immunomodulation in sepsis - A case report. Indian J Transplant 2021;15:73-5

How to cite this URL:
Madarasu RC, Kumthekar GV. Immunomodulation in sepsis - A case report. Indian J Transplant [serial online] 2021 [cited 2021 Jul 30];15:73-5. Available from: https://www.ijtonline.in/text.asp?2021/15/1/73/312749






  Introduction Top


Sepsis and septic shock affect anywhere between 100 and 1000/100,000 person-years and 19/100,000 person-years depending on the cohort studied, with mortality rates ranging between 20% and 50%.[1] The recently updated Sepsis 3.0 consensus definitions state that sepsis is an infection accompanied by life-threatening organ dysfunction caused by a dysregulated host response. Given the pivotal role of cytokine production in sepsis and post major surgery, it follows that removal of these substances may attenuate the response particularly in the early phase of sepsis.[2] Many theories such as peak concentration hypothesis,[3] cytokinetic theory,[4] and cytotoxic immune–threshold immune modulation[5] have been proposed. Indeed, blood level of mediators (more than cytokines) implies the saturation of the interstitial and cellular compartments to be present in the blood. It is the so-called tip of the iceberg theory.[6]

Basic research and clinical studies performed over the past several years have led to a significant amount of data on immunoregulatory and modulating mechanisms in sepsis. Therefore, it would appear to be highly promising and beneficial to therapeutically target these mediators to decrease the unfavorable effects of sepsis-related host responses and to improve the overall outcome. The Acute Dialysis Quality Initiative (ADQI) Bogotá consensus concluded that blood purification might offer potential advantages over alternative therapies for sepsis. However, the ADQI acknowledges that slow progress has been made, in part due to a failure to phenotype patients in clinical trials.[7]

The three main blood purification techniques available are filtration, dialysis (diffusion), and adsorption. Continuous venovenous hemofiltration (CVVH) with dialysis or continuous hemodiafiltration were first used for the treatment of hypercytokinemia in 1993. There are a multitude of adsorption hemofilters currently being investigated including, but not limited to, polymethyl-methacrylate membranes, AN69 surface-treated (AN69ST) membranes, and modified AN69ST membranes (oXiris®). The oXiris membrane is intended to adsorb both endotoxin and cytokines, and it has been shown to adsorb more of both when compared with the AN69 membrane. Although initial results using Polymyxin B hemoperfusion showed promise, this has not been borne out by subsequent randomized clinical trials.[8] Among adsorbent technologies, we have CytoSorb as a hemadsorption device. The adsorber has a surface area of about 45,000 m2 compared to a conventional hemofilter with a surface area of 1–1.5 m2 with a molecular cutoff of about 60 kDa removing cytokines as well as other toxins and drugs. This size range (referred to as the “cytokine sweet spot”) targets many of the key inflammatory mediators involved in the sepsis-triggered cytokine storm, such as interleukin (IL)-1 β, IL-6, tumor necrosis factor-alpha (TNF-α), IL-10, and potentially Pathogen-associated molecular patterns (PAMP) and damage-associated molecular patterns (DAMP). CytoSorb does not adsorb endotoxin which has a molecular weight of 100 kDa. CytoSorb is saturable regarding adsorption in the clinical setting (mostly after 8 h) as evidenced by a rebound increase in the dose of vasopressors.


  Case Report Top


We comment on a peculiar scenario of using extracorporeal blood purification in a patient undergoing cardiac transplantation. This was a case of cardiac transplantation going through a cytokine storm like situation. Medical management with immunosuppressants was not justified and using extracorporeal removal of inflammatory markers was very much indicated. As the cause of immune dysregulation was evident and CytoSorb was used within the appropriate time window, clinical recovery time was shortened. Subclassifying sepsis and septic shock proved beneficial for the patient selection, duration of therapy, and selecting endpoints of cytokine removal through blood purification.


  Discussion and Conclusion Top


Sepsis is a syndrome with two extremes of immune responses. On the one hand, we have excessive immune activation (cytokine storm) which appears earlier than excessive immunosuppression (immune paralysis). Obviously, cytokine removal translates into clinical benefits if employed early in the course as shown by trials such as EUPHRATUS[9] and ACESS.[10] To diagnose cytokine storm, multiple biomarkers are shown to be useful, such as IL-6, TNF-α, IL-10, IL-1, and procalcitonin. How best we utilize them and incorporate in daily practice remains elusive and hence subject to further research [Table 1].
Table 1: Options for extracorporeal removal of cytokine and endotoxin in sepsis

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Cytokine absorption is also studied in pre- and postorgan transplantation. The influence of intraoperative cytokine adsorption on the perioperative vasoplegia, inflammatory response, and outcome was studied during orthotopic heart transplantation (OHT). Eighty-four OHT patients were separated into the cytokine adsorption-treated group or controls. No difference in adverse events was observed between the two groups. The frequency of renal replacement therapy was less in the cytokine adsorption-treated patients than in the controls. Intraoperative cytokine adsorption treatment was associated with reduced vasopressor demand with a favorable tendency in length of mechanical ventilation, intensive care unit stay, and renal replacement therapy.[11] In kidney and liver transplantation, cytokine removal is mainly therapeutic and not prophylactic. Moreover, indications are the same as in the general population. Role of cytokine removal as a prophylactic or a therapeutic modality in other solid organ transplantations and haematopoietic stem cell transplantation is a topic worth exploring. As of now, posttransplantation sepsis and organ dysfunction have similar indications and utility of cytokine removal as in the general population.[12]

Indeed, as our understanding of the immune dysregulation and cytokine storm in sepsis increases, the different in vitro adsorption properties of oXiris, Toraymyxin, and CytoSorb could enable treatment to be more tailored to patients. CytoSorb and other hemoadsorption devices work in a concentration-dependent manner and only patients with high serum cytokine loads may benefit from this therapy. Early initiation of therapy (preferably within 24 h) also appears to be important, improving hemodynamic stability and lowering the predicted rate of mortality.[13]

Immunomodulation implies that we know which phase of sepsis a patient belongs. Cytokine removal will benefit those who are with cytokine storm (hypercytokinemia) and may not benefit those with sepsis-induced immunosuppression. Contrary to present understanding, cytokine storm may appear anywhere in disease trajectory and essentially not at the beginning. Hence, we target patient population with dyscytokinemia and target molecules for extracorporeal removal (cytokines ± endotoxins) while prescribing these not so novel therapies in sepsis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Honore PM, Hoste E, Molnár Z, Jacobs R, Joannes-Boyau O, Malbrain MLNG, et al. Cytokine removal in human septic shock: Where are we and where are we going? Ann Intensive Care 2019;9:56.  Back to cited text no. 1
    
2.
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016;315:801-10.  Back to cited text no. 2
    
3.
Ronco C, Tetta C, Mariano F, Wratten ML, Bonello M, Bordoni V, et al. Interpreting the mechanisms of continuous renal replacement therapy in sepsis: The peak concentration hypothesis. Artif Organs 2003;27:792-801.  Back to cited text no. 3
    
4.
Peng ZY, Bishop JV, Wen XY, Elder MM, Zhou F, Chuasuwan A, et al. Modulation of chemokine gradients by apheresis redirects leukocyte trafficking to different compartments during sepsis, studies in a rat model. Crit Care 2014;18:R141.  Back to cited text no. 4
    
5.
Cole L, Bellomo R, Journois D, Davenport P, Baldwin I, Tipping P. High-volume haemofiltration in human septic shock. Intensive Care Med 2001;27:978-86.  Back to cited text no. 5
    
6.
Cavaillon JM, Munoz C, Fitting C, Misset B, Carlet J. Circulating cytokines: The tip of the iceberg? Circ Shock 1992;38:145-52.  Back to cited text no. 6
    
7.
Kellum JA, Gómez H, Gómez A, Murray P, Ronco C; ADQI XIV Workgroup. Acute Dialysis Quality Initiative (ADQI) XIV Sepsis Phenotypes and Targets for Blood Purification in Sepsis: The Bogotá Consensus. Shock 2016;45:242-8.  Back to cited text no. 7
    
8.
Sun S, Sursal T, Adibnia Y, Zhao C, Zheng Y, Li H, et al. Mitochondrial DAMPs increase endothelial permeability through neutrophil dependent and independent pathways. PLoS One 2013;8:e59989.  Back to cited text no. 8
    
9.
Dellinger RP, Bagshaw SM, Antonelli M, Foster DM, Klein DJ, Marshall JC, et al. Effect of targeted polymyxin B hemoperfusion on 28-day mortality in patients with septic shock and elevated endotoxin level: The EUPHRA- TES randomized clinical trial. JAMA 2018;320:1455-63.  Back to cited text no. 9
    
10.
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. Crit Care 2018;22 Suppl 1:82.  Back to cited text no. 10
    
11.
Nemeth E, Kovacs E, Racz K, Soltesz A, Szigeti S, Kiss N, et al. Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation – An observational study. Clin Transplant 2018;32:e13211.  Back to cited text no. 11
    
12.
Friedman BH. Serum cytokine profiles associated with early allograft dysfunction in patients undergoing liver transplantation. Liver Transpl 2012;18:166-76.  Back to cited text no. 12
    
13.
Bonavia A, Groff A, Karamchandani K, Singbartl K. Clinical utility of extracorporeal cytokine hemoadsorption therapy: A literature review. Blood Purif 2018;46:337-49.  Back to cited text no. 13
    



 
 
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