|Year : 2021 | Volume
| Issue : 1 | Page : 73-75
Immunomodulation in sepsis - A case report
Rajasekara Chakravarthi Madarasu, Girish Vasudeo Kumthekar
Department of Nephrology, Star Hospitals; Renown Clinical Services, Hyderabad, Telangana, India
|Date of Submission||10-Apr-2020|
|Date of Acceptance||30-Dec-2020|
|Date of Web Publication||31-Mar-2021|
Dr. Rajasekara Chakravarthi Madarasu
Department of Nephrology, Star Hospitals, Road No 10, Banjara Hills, Hyderabad, Telangana
Source of Support: None, Conflict of Interest: None
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
| Introduction|| |
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%. 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. Many theories such as peak concentration hypothesis, cytokinetic theory, and cytotoxic immune–threshold immune modulation 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.
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.
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. 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|| |
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|| |
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 and ACESS. 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. 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.
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.
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
Conflicts of interest
There are no conflicts of interest.
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