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 Table of Contents  
PERSPECTIVE
Year : 2022  |  Volume : 4  |  Issue : 1  |  Page : 13

Endotoxemic Sepsis: Clinical Features and Therapy


1 Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Spectral Medical, Toronto, Ontario, Canada
2 Toray Medical Co., Ltd., Tokyo, Japan
3 Spectral Medical, Toronto, Ontario, Canada

Date of Submission30-Apr-2022
Date of Acceptance07-May-2022
Date of Web Publication11-Jul-2022

Correspondence Address:
Dr. John A Kellum
Spectral Medical Inc., 135 The West Mall, Unit 2, Toronto, Ontario M9C 1C2

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JTCCM-D-22-00015

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  Abstract 


Heterogeneity in clinical presentation for patients with sepsis complicates treatment and prognosis and limits the development of new therapy. Reasons for this heterogeneity is unclear but recent studies have identified sub-types sepsis defined by clinical features. These sub-types may be brought about by certain triggers such as endotoxin and may further require a susceptible host. Treatment with hemoperfusion to remove endotoxin is discussed.

Keywords: Organ failure, endotoxin, hemoperfusion, blood purification, shock, phenotype, endophenotype


How to cite this article:
Kellum JA, Shoji H, Foster D, Walker PM. Endotoxemic Sepsis: Clinical Features and Therapy. J Transl Crit Care Med 2022;4:13

How to cite this URL:
Kellum JA, Shoji H, Foster D, Walker PM. Endotoxemic Sepsis: Clinical Features and Therapy. J Transl Crit Care Med [serial online] 2022 [cited 2022 Dec 8];4:13. Available from: http://www.tccmjournal.com/text.asp?2022/4/1/13/350634




  Introduction Top


Sepsis is currently defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.[1] This definition has operational weaknesses in that no criteria are available to determine whether the host response is dysregulated and the attribution of organ failure to infection, rather than comorbidity or the results of treatment, can be tenuous. Furthermore, marked heterogeneity may exist from patient to patient both in terms of distribution of organ dysfunction and its severity. Such heterogeneity could be explained by the presence of multiple subtypes of sepsis that may be brought about by different triggers and may have important implications for treatment.

Endotoxin is a lipopolysaccharide component of the outer cell membrane of Gram-negative bacteria. Endotoxin can trigger both a brisk host response and multiple types of acute organ failure. Interestingly, endotoxin sensitivity varies widely across the animal kingdom and humans are exquisitely sensitive to endotoxin when compared to other animals. This sensitivity appears to be a recent evolutionary adaptation as humans are much more sensitive, 10–100-fold so, than even other primates.[2] Endotoxin in the bloodstream, or endotoxemia, is commonly increased in patients with sepsis, especially septic shock, and appears to result much more from translocation of bacterial products from the gut than from live organisms in the blood – indeed more than 70% of patients with endotoxemic septic shock have negative blood cultures.[3] Furthermore, viral sepsis (e.g., COVID-19) may also lead to endotoxemia.[4] Most endotoxin rapidly becomes sequestered by molecules such as lipopolysaccharide-binding protein and high-density lipoprotein cholesterol such that “free endotoxin” is relatively scarce even when exposure is high. Still, the overall burden of endotoxin is related to survival. Endotoxin can be measured in whole blood using the endotoxin activity assay (EAA) and high endotoxin activity increases the risk of death.[5]

For this reason, several investigators have sought to neutralize endotoxin using various pharmacologic approaches – from monoclonal antibodies to compounds derived from endotoxin neutralizing substances such as lactoferrin.[6] An alternative approach is to remove the endotoxin directly from the bloodstream using polymyxin B-hemoperfusion (PMX-HP). While definitive evidence from large, randomized trials is unavailable, data from over 30 years of clinical use indicate a potential to improve survival over the standard of care.[7],[8]


  Pathophysiology of Sepsis Top


The pathophysiology of sepsis is complex and incompletely understood.[9] As the definition of sepsis states, the host response is “dysregulated.” Both innate and adaptive immunity play a role, but dysregulation is mainly defined in terms of innate immunity and two major components of the innate response are inflammation and complement. Inflammation plays a critical role in the pathogenesis of sepsis, with an initial release of cytokines, damage-associated molecular patterns (DAMPs), and pathogen-associated molecular patterns (PAMPs) in response to invasive pathogens. PAMPs stimulate monocytes to release procoagulants and other mediators to activate platelets, neutrophils, and endothelial cells. DAMPs, comprised of histones, chromosomal DNA, mitochondrial DNA, nucleosome, and a variety of proteins released from neutrophils which activate inflammation and coagulation. Pathogens, particularly bacteria, have evolved in symbiosis with humans and PAMPs are particularly well-suited to cause systemic inflammation. Endotoxin activates the immune response through multiple pathways, including some shared by DAMPs. Complement is so named for its ability to complement the function of immune effector cells to clear damaged cells, destroy pathogens and promote inflammation. The complement system (or cascade) is an ancient system, evolutionarily conserved, and consists of several small proteins that are synthesized by the liver, and circulate in the blood as inactive precursors. When activated, proteases in the system cleave specific proteins to initiating and amplifying a cascade, ultimately resulting in stimulation of phagocytes to clear foreign and damaged material, inflammation to attract additional phagocytes, and activation of the so-called “membrane attack complex” which is directly cytotoxic.

Because inflammation on a systemic level is dangerous, endogenous regulatory mechanisms also exist and are vital for survival. Both pro- and anti-inflammatory cytokines are released, and engagement of complement and coagulation cascades have built-in “breaking mechanisms” ensuring these systems are controlled. Inherited and acquired, result in severe clinical manifestations. For example, hemolytic-uremic syndrome (HUS) is a form of uncontrolled complement activation and results in thrombotic microangiopathy, resulting in hemolytic anemia and multiple-organ failure predominantly involving the kidneys, brain, and gastrointestinal (GI) tract. Macrophage activation syndrome (MAS) is a form of “runaway inflammation” due to a defect in natural killer cells and leads to a condition sometimes referred to as cytokine storm. Refractory fever, liver injury, hepatosplenomegaly together with endothelial dysfunction (thrombocytopenia plus coagulopathy) are characteristics of MAS.


  Novel Sepsis Phenotypes Top


In sepsis, marked heterogeneity exists from patient to patient both in terms of distribution of organ dysfunction and its severity. Such heterogeneity could be explained by the presence of multiple subtypes (endophenotypes) of sepsis that may have important implications for treatment. Interestingly, phenotypes resembling both of HUS and MAS have been described in both adults and children with sepsis and genetic markers may be present for both.[10],[11],[12],[13] For example, atypical HUS (aHUS) encompasses a group of disorders that results from dysregulation of the alternative complement pathway but are not caused by Shiga toxin-producing  Escherichia More Details coli, which characterizes STEC-HUS. Up to 60% of patients with aHUS have an identifiable pathogenic gene variant in the complement pathway.[14] In an analysis of more than a thousand adult patients with sepsis, serum ferritin was used to select patients with severe inflammation and six were subjected to whole-exome sequencing. All six exhibited one or more pathologic or potentially pathologic gene variant and half had variants associated with aHUS (the other half, interestingly, associated with MAS).[12] However, aHUS is known to have incomplete genetic penetrance, with only 40%–50% of carriers with known pathogenic variants going on to develop the clinical syndrome. It is therefore proposed that aHUS occurs following a trigger event, such as infection or other events that activates complement. Unregulated complement activation ultimately results in the formation of the C5b-C9 membrane attack complex, leading to more endothelial injury and the formation of microvascular thrombi.[14]

Similarly, MAS is life-threatening complication of systemic inflammatory disorders, most commonly systemic juvenile idiopathic arthritis or Still's disease in adults, as well as systemic lupus erythematosus. Several investigators from around the world have described “MAS features” in association with some severe cases of sepsis in both adults and children. Shakoory et al. performed a post hoc analysis of a prior sepsis trial and found that anakinra (Interleukin-1 receptor antagonist) improved mortality in a subset of patients with MAS features defined by disseminated intravascular coagulation (DIC) together with liver dysfunction.[11] The MAS phenotype was present in 5.6% of the sepsis population and treatment with anakinra reduced the 28-day mortality in this subgroup from 64.7% to 34.6% (P < 0.05).[11] More recently, Anderko et al.[13] reported that 6% of patients with septic shock in the ProCESS trial[15] (n = 82/1341) had this same MAS phenotype, which was an independent risk factor for 90-day mortality (odds ratio = 4.19, 95% confidence interval [CI] = 1.13–16.39, P = 0.034). Relative to sepsis controls, the MAS cohort demonstrated increased levels of 21 of the 26 MAS-associated biomarkers (P < 0.05). This panel was highly predictive of both the MAS phenotype (sensitivity = 82%, specificity = 84%) and mortality (sensitivity = 92%, specificity = 90%). The authors concluded that liver dysfunction plus DIC identifies patients with sepsis who might benefit from MAS-directed therapies.[13]

Identification of these syndromes is important because specific therapies exist. Anti-C5 monoclonal Ab (eculizumab) is now standard therapy for aHUS and other drugs targeting complement are being developed. For MAS, the traditional treatments of high-dose steroids, cyclosporin and even etoposide in refractory cases are being replaced by various specific therapies, including IL-1 receptor antagonist (Anakinra, Canakinumab); Anti-IL-6R monoclonal Ab (Tocilizumab); IL-18-binding protein; CTLA4-Ig (Abatacept); and JAK inhibitor (Tofacitinib). Significant experience has been gained with these therapies for the management of COVID-19, though results have been variable, perhaps related to the absence of careful selection of patients with MAS.


  Sepsis Phenotypes Using Artificial Intelligence Top


Important conformation that endophenotypes of sepsis are likely comes from studies using large datasets and artificial intelligence. Seymour et al.[16] analyzed data from over 60,000 patients and used machine learning to derive 4 novel sepsis phenotypes (α, β, γ, and δ) with different demographics, laboratory values, and patterns of organ dysfunction.[16] In simulations using data from three randomized clinical trials involving 4737 patients, the outcomes related to the treatments were sensitive to changes in the distribution of these phenotypes. Compared to other phenotypes, the δ-phenotype, occurring in up to 15% of patients, is characterized by greater rates of acute kidney injury (AKI), hepatic dysfunction, and endothelial dysfunction. Kidney disease is a prominent feature of both the β and δ phenotypes. However, for the β phenotype chronic kidney disease predominates (as well as acute-on-chronic), whereas AKI is more common and more severe in the δ phenotype. Mortality rates are much greater with the δ-phenotype 32% at hospital discharge compared to 2% for the α-phenotype.[16] These phenotypes are not related to the site of infection or the organism but are correlated with inflammation (γ and δ being much higher than α and β). The distribution of patients exhibiting each phenotype is very consistent overtime 30%–35% α, 25% each β and γ, and 10%–15% δ. However, mortality corresponding to these phenotypes has all improved dramatically over the last two decades with the exception of the δ phenotype, which remains above 40% and has been unchanged. For example, in patients enrolled in a trial of drotrecogin alpha reported in 2001,[17] patients with the α phenotype experienced a 15% 28-day mortality.[16] In a trial of early goal-directed therapy reported in 2014,[15] the α phenotype resulted in a mortality of only 6% at 28 days. Conversely, mortality was approximately 40% for the δ phenotype in both trials.[16]

Qin et al.[18] used a similar approach (k-means clustering analysis) on the dataset of 404 children. Four phenotypes were derived using 25 available bedside variables, including C-reactive protein and ferritin (PedSep-A, B, C, and D).[18] The PedSep-A phenotype was almost identical to the α phenotype described by Seymour et al.[16] and occurred in 33%, strikingly similar to the proportion of adults with the α phenotype. Patients were younger and previously healthy, with the lower C-reactive protein and ferritin levels, the higher lymphocyte and platelet counts, compared to other phenotypes. Mortality was only 2%. Similarly, the PedSep-D phenotype was almost identical to the δ phenotype described by Seymour et al.,[13],[16] in which renal, hepatic, and hematologic organ failure were most common. Strikingly, the proportions of children with the PedSep-D phenotype and adults with the δ phenotype were almost identical at ~14%. Like the δ phenotype, mortality was highest for the PedSep-D phenotype, a staggering 34%. Furthermore, Qin et al.[18] determined the relative rates of thrombotic microangiopathy (i.e., aHUS-like) and MAS-like syndromes for patients with each phenotype and found much higher rates within the PedSep-D phenotype-adjusted odds ratios of 47.51 (95% CI 18.83–136.83), P < 0.0001; and 38.63 (95% CI 13.26–137.75), P < 0.0001, respectively.[16]


  Mechanism-Derived Therapy for Sepsis Endotypes Top


Establishing molecular pathogeneses for subtypes of sepsis could lead to breakthrough therapies. Complement activation is an attractive target because of existing therapies (e.g., eculizumab), although complement inhibition in the setting of active infection would be dangerous. The multiple therapies developed for MAS are being reevaluated for sepsis in the wake of experience with COVID-19. The δ-phenotype described by Seymour et al.[13],[16] appears to have features consistent with both aHUS and MAS and may include both phenotypes.

Interestingly, aHUS and MAS, together forming the bulk of the δ and PedSep-D phenotypes, may have a common pathogenesis. Endotoxin is an important molecular target for these phenotypes because endotoxin activates both complement and cytokines. Animal models routinely rely on high-dose endotoxin, and in an unusual case of self-injection intravenously of high-dose endotoxin, a patient developed profound shock, AKI, hepatic and endothelial dysfunction with relatively spared pulmonary and neurologic function.[19] Endotoxin contributes to the pathophysiology of sepsis and in patients with septic shock; a third to a half of patients exhibit high levels of endotoxin activity in their blood.[3] This signal is not related to primary bloodstream infection and appears instead to result from barrier dysfunction in the gastrointestinal track with translocation of endotoxin into the circulation. Evidence that the effects of endotoxemia may be reversible comes from a case report by Akitomi et al.[20] These authors describe whole blood gene expression profiling in a patient with sepsis treated with PMX-HP to remove circulating endotoxin. Comparative gene expression analysis of whole blood from the patient identified 867 upregulated genes and 1467 downregulated ones. Upregulated genes were found to be involved in oxidative stress, whereas those downregulated were related to neutrophil defensins, tumor necrosis factor-α/nuclear factor-κB, interleukin-8, and interleukin-6 signaling cascades, and pyruvate metabolism.

Endotoxin activity can be measured by the FDA-approved assay, EAA, and in the EUPHRATES trial, patients were enrolled who exhibited endotoxin activity ≥0.6 units.[21] Compared to the ProCESS trial,[15] which enrolled the same clinical phenotype of septic shock but without the EAA, patients in EUPHRATES exhibited much higher rates of AKI, liver dysfunction and thrombocytopenia with or without DIC [Table 1].
Table 1: Comparison of the early use of polymyxin-B hemoperfusion in a randomized trial of adults treated for endotoxemia in septic shock study[3] and protocolized care for early septic shock[15] trials for clinical features associated with atypical hemolytic uremic syndrome and macrophage activation syndrome

Click here to view



  Clinical Experience with Hemoperfusion Using Polymyxin B Hemoperfusion Top


In many parts of the world, especially in Japan and Italy, extracorporeal blood purification modalities are used to remove endotoxin from the bloodstream. PMX-HP is currently the most widely used endotoxin removal therapy for the treatment of sepsis and septic shock. The mechanism for PMX-HP is endotoxin adsorption through a binding interaction between the lipid A portion of the lipopolysaccharide (endotoxin) molecule and the polymyxin B molecule.[22] The PMX-HP procedure is simple and consists of whole blood circulation at a blood flow rate of 80–120 mL/min using an anticoagulant infusion such as unfractionated heparin [Figure 1].
Figure 1: This figure illustrates the treatment procedure for PMX-HP. As a blood access, a double lumen catheter is inserted into a central vein. Extracted whole blood via a double-lumen catheter is perfused through an endotoxin removal cartridge, Toraymyxin. Blood flow rate is 80–120 mL/min and anticoagulant such as heparin is required

Click here to view


Ikeda et al.[23] assessed the severity of endotoxemia in critically ill patients using EAA.[23] They evaluated 314 critically ill patients admitted to the intensive care unit (ICU). Patients were stratified into four EAA groups of very low (EAA < 0.2), low (0.2 ≤ EAA < 0.4), intermediate (0.4 ≤ EAA < 0.6) and high (≥0.6 EAA), respectively. The severity of illness based on the mean APACHE II score at ICU admission was increased in parallel with increased EAA levels. The percentage of the patients diagnosed with sepsis or septic shock were 19.3% (very low EAA), 34.5% (low EAA), 50.0% (intermediate EAA), and 81.3% (high EAA). Mortality was highly correlated with EAA as well. The 28-day mortality was 12.0%, 16.1%, 31.3%, and 31.3% respectively.

PMX-HP is highly effective in endotoxin removal and large registries amassed over the last three decades show a consistent, albeit small, improvement in survival in unselected patients with septic shock.[7] Fujimori et al.[7] analyzed the efficacy of PMX-HP on adult sepsis patients using the Japanese Diagnosis Procedure Combination database (a large-scale inpatient database).[7] Of 44,177 adult sepsis patients, 2191 patients received PMX-HP therapy. Propensity score matching produced 2033 patient pairs. The patients were then stratified into five Sequential Organ Failure Assessment (SOFA) score categories based on the baseline SOFA score, 0–6, 7–9, 10–12, 13–15, 16–24, respectively. The 28-day survival benefit for PMX-HP-treated groups was significantly improved in the SOFA score category of 7–9 (mortality: PMX-HP 15.0%; Control 19.9%, P = 0.04); and 10–12 (mortality: PMX-HP 18.6%; Control 27.4%, P = 0.0008). There was neither survival benefit in lower SOFA score ranges nor in the highest intervals. Organ support-free days, such as ventilator-free days, noradrenalin-free days, and continuous renal replacement-free days, were significantly greater for PMX-HP compared to control when the SOFA score was 7–9 and 10–12. Thus, this study identifies a patient population with sepsis or septic shock who is most likely to benefit from PMX-HP therapy.

While the randomized controlled trials for PMX-HP did not consistently demonstrate the improvement of 28-day all-cause mortality, the Early Use of Polymyxin-B Hemoperfusion in a Randomized trial of Adults Treated for Endotoxemia in Septic shock study (EUPHRATES) in North America also demonstrated that a well-defined subgroup of patients, showed a 10.7% absolute risk reduction for mortality with PMX-HP treatment versus control.[21] Patients in the EUPHRATES study with a severity of illness indicator (the MODS score) of >9 and with a treatable EAA level of 0.60–0.89 are now the eligible population in the follow-on Tigris clinical study, which is currently ongoing in the US (NCT03901807).

In the recent SARS-CoV-2 pandemic, there are numerous reports of high levels of endotoxin (≥0.60) measured using the EAA in patients admitted to the ICU with severe COVID-19 infection.[4],[24],[25] Interestingly, several investigators have found evidence of viral-bacterial interaction enhancing viral pathogenicity.[26] Viruses can bind to LPS, thereby enhancing their attachment to various molecules on the surface of host cells, including ACE2. Such interactions can dramatically increase the viral infectivity and resulting inflammation.[27],[28] Petruk et al.[29] found that SARS-CoV-2 can directly interact with LPS through its S protein.[29] The combination of S protein with even low levels of LPS increases NF-kB activation and the subsequent cytokine response in monocytic cells in vitro.[29]

PMX-HP has also been used in small numbers of patients with COVID-19. De Rosa et al.[30] reported 12 COVID-19 patients with endotoxic shock from the Early Use of Polymyxin B Hemoperfusion in Abdominal Septic Shock 2 (EUPHAS2) registry[30] and other studies have reported PMX-HP being used for critically ill COVID-19 patients.[24],[31] SOFA score improvements were seen following PMX-HP, including reductions in vasopressor dependency.


  Conclusion Top


Endophenotypes of sepsis have been described and may reflect underlying pathology linked to complement activation and natural killer cell dysfunction. Endotoxemia could be the “missing link” in the pathogenesis of these cases. Clinical experience with endotoxin removal using PMX-HP has been accumulating for the past three decades. The effectiveness of PMX-HP therapy by decreasing the burden of endotoxin is consistently being reported in many clinical studies. As with so many other critical disease syndromes, the use of PMX-HP must be prescribed for those most likely to benefit. Targeting a treatment window based on the presence of endotoxemia and signs of increased severity of illness is the next important step toward the search for a successful therapy in sepsis.

Financial support and sponsorship

Nil.

Conflicts of interest

John A. Kellum and Debra Foster are employees and stockholders of Spectral Medical. Paul M. Walker is a member of the board and holds stock in Spectral Medical. Hisataka Shoji is an employee of Toray Medical.



 
  References Top

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Fujimori K, Tarasawa K, Fushimi K. Effectiveness of polymyxin B hemoperfusion for sepsis depends on the baseline SOFA score: A nationwide observational study. Ann Intensive Care 2021;11:141.  Back to cited text no. 7
    
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Fujimori K, Tarasawa K, Fushimi K. Effects of polymyxin B hemoperfusion on septic shock patients requiring noradrenaline: Analysis of a nationwide administrative database in Japan. Blood Purif 2021;50:560-5.  Back to cited text no. 8
    
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Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: Reanalysis of a Prior Phase III Trial. Crit Care Med 2016;44:275-81.  Back to cited text no. 11
    
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Kernan KF, Ghaloul-Gonzalez L, Shakoory B, Kellum JA, Angus DC, Carcillo JA. Adults with septic shock and extreme hyperferritinemia exhibit pathogenic immune variation. Genes Immun 2019;20:520-6.  Back to cited text no. 12
    
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Katagiri D, Ishikane M, Asai Y, Izumi S, Takasaki J, Katsuoka H, et al. Direct hemoperfusion using a polymyxin B-immobilized polystyrene column for COVID-19. J Clin Apher 2021;36:313-21.  Back to cited text no. 31
    


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