Treatment Advances in Sepsis and Septic Shock

Treatment Advances in Sepsis and Septic Shock: History

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Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection, and it affects over 25 million people every year. Even more severe, septic shock is a subset of sepsis defined by persistent hypotension, and hospital mortality rates are higher than 40%. As new pathophysiological mechanisms have been uncovered, immunostimulatory therapy has emerged as a promising path forward. Highly investigated treatment strategies include cytokines and growth factors, immune checkpoint inhibitors, and even cellular therapies.

sepsis
septic shock
inflammation
immunomodulation

1. Introduction

Since 2016, sepsis has been defined as “life-threatening organ dysfunction caused by a dysregulated host response to infection” and is represented as an increase of 2 or more points in the Sequential Organ Failure Assessment (SOFA) score ^[1]. In these patients, a dysregulated immune response can lead to an exaggerated pro-inflammatory process, immunosuppression, and/or persistent immune disruption ^[2]. Even more severe, septic shock is currently defined as a “subset of sepsis in which underlying circulatory and cellular metabolism abnormalities are profound enough to substantially increase mortality” and is associated with hospital mortality rates higher than 40% ^[1]. Patients with septic shock are characterized by persistent hypotension despite adequate volume resuscitation, the need for vasopressor therapy, and lactate >2 mmol/L ^[1]^[3]. The resulting metabolic dysfunction and inadequate tissue perfusion may ultimately lead to multiorgan failure and death ^[4]^[5].

Data from 2018 show sepsis affects approximately 27–30 million people worldwide, resulting in 6–9 million deaths every year ^[5], and while the real incidence and mortality attributed to sepsis are unknown, there is little doubt that it represents a significant challenge ^[1]^[3]^[6]. New treatment protocols and advancements in therapeutic approaches shifted the paradigm towards a more chronic, immunosuppressive stage of the disease ^[7], responsible for much of the later-stage morbidity and mortality. Importantly, epidemiological data on the incidence and mortality of sepsis is typically extrapolated from high-income countries, making it difficult to determine the true burden of this syndrome ^[6].

In the short term, sepsis survivorship is increasing ^[8]^[9]. The Surviving Sepsis Campaign (SSC), recently updated in 2021, provides evidence-based guidelines on identifying and treating these patients ^[10], which have contributed to reducing in-hospital mortality ^[3]. These guidelines provide guidance on the administration of antibiotics, appropriate source control interventions, fluid and vasopressor therapy, and other adjuvant measures. However, even though 50% of sepsis survivors recover once they are discharged from the hospital, one-third die within the next year, and one-sixth develop persistent cognitive impairment ^[11]^[12]^[13]. In the coming years, late-sepsis mortality is expected to increase ^[14] and disproportionately affect the growing elderly population, who often have weakened immune systems and other comorbidities ^[15]. No sepsis-specific therapies exist, and new approaches are urgently needed ^[16]^[17].

As decades of clinical trials targeting hyperinflammation have been somewhat unsuccessful and new pathophysiological mechanisms have been uncovered, the focus of more recent research has shifted to the immunosuppressive phase of sepsis and novel immunomodulatory therapies. Remarkably, anti-inflammatory therapies such as cytokine blockers have recently shown tremendous success in severe COVID-19 ^[18], a sepsis-like illness characterized by an imbalanced immune response ^[19]. Since the voluntary withdrawal of the marketing authorization of drotrecogin alpha (activated) (DAA) due to unsuccessful results of the post-authorization measures delineated for this product ^[20], no other therapies have been approved specifically for the indication of sepsis or septic shock ^[21].

Patients with sepsis typically present with a highly dysregulated immune system that fluctuates from a state of excessive inflammation to one of immunosuppression. In the case of sepsis, clinically relevant biomarkers must correctly identify each patient’s individual immune balance ^[22]—adequate stratification is needed to ensure the correct patient is receiving the appropriate treatment at the right time. Through transcriptomic profiling, two different immune phenotypes have been recognized in sepsis ^[23]: sepsis response signature (SRS)1 or SRS2. While the SRS2 phenotype is relatively immunocompetent, SRS1 identified patients with a more immunosuppressed profile, characterized by T-cell exhaustion, endotoxin tolerance, and low leukocyte HLA-DR expression. Similar results have also been described by Wang et al. ^[24]. However, of the 258 biomarkers that have been identified over the past decade ^[25]^[26], none have shown the necessary sensitivity and specificity to be used in routine clinical practice.

2. Modulating the Host Response to Sepsis

As multiple studies have shown that the immune response is not linear, revised models of sepsis pathophysiology have been proposed, with Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) being the most relevant one ^[27]^[28]. In these patients, immunosuppression coexists with low-grade inflammation, making it difficult to target either phase of the immune response. Since traditional treatment strategies have been insufficient to curb long-term mortality, immunoadjuvant therapy has emerged as a promising way forward and research focus has largely shifted into targeting specific mechanisms of sepsis pathophysiology.

Following the methodology described above, the coming sections summarize the major alterations in the host response during sepsis and provide a rationale for potential therapeutic interventions. A compilation of recent clinical trials on the subject is provided in Table 1 and Table 2.

Table 1. Completed interventional studies for the treatment of sepsis and septic shock from the last 10 years.

Title	ClinicalTrials.gov Identifier	Intervention	Phase (Participants)	Study Design	Primary Outcome	Study Start Date	Study Progress	Primary Sponsor	Ref.
Studying Complement Inhibition in Early, Newly Developing Septic Organ Dysfunction	NCT02246595	CaCP29	Phase 2 (n = 72)	Quadruple-blinded, randomized, parallel assignment, placebo-controlled trial	1. Plasma concentration of CaCP29 2. Pharmacodynamic effects of CaCP29 on the change from baseline in plasma concentrations of C5a 3. Safety variables	April 2014	Completed, No Results Posted	InflaRx GmbH	^[29]
In Vivo Effects of C1-esterase Inhibitor on the Innate Immune Response During Human Endotoxemia	NCT01766414	C1-esterase inhibitor	Phase 3 (n = 20)	Triple-blinded, randomized, parallel assignment, placebo-controlled trial (unspecified blinding)	Neutrophil phenotype and redistribution	September 2013	Completed, No Results Posted	Radboud University Medical Center	^[30]
Vorapaxar in the Human Endotoxemia Model	NCT02875028	Vorapaxar	Phase 4 (n = 16)	Quadruple-blinded, randomized, crossover assignment, placebo-controlled trial	Changes in Prothrombin Fragments F1+2	June 2016	Completed	Medical University of Vienna	^[31]
A Trial of Validation and Restoration of Immune Dysfunction in Severe Infections and Sepsis	NCT03332225	Anakinra; Recombinant human interferon-γ	Phase 2 (n = 36)	Quadruple-blinded, randomized, parallel assignment, placebo-controlled trial	28-day mortality	December 2017	Completed, No Results Posted	Hellenic Institute for the Study of Sepsis	^[32]
A Study of IL-7 to Restore Absolute Lymphocyte Counts in Sepsis Patients	NCT02640807	CYT107: Interleukin-7	Phase 2 (n = 27)	Quadruple-blinded, randomized, parallel assignment, placebo-controlled trial	Immune reconstitution of lymphocytopenic sepsis patients	January 2016	Completed	Revimmune	^[33]
GM-CSF to Decrease ICU Acquired Infections	NCT02361528	GM-CSF	Phase 3 (n = 166)	Quadruple-blinded, randomized, parallel assignment, placebo-controlled trial	Number of patients presenting at least one ICU-acquired infection at D28 or ICU discharge	September 2015	Completed, No Results Posted	Hospices Civilis de Lyon	^[34]
Efficacy of Thymosin Alpha 1 on Improving Monocyte Function in Sepsis	NCT02883595	Thymosin Alpha 1	Phase 4 (n = 20)	Quadruple-blinded, randomized, parallel assignment, placebo-controlled trial	Flow cytometric measuring of phagocytosis (CD11b, CD64), antigen presenting (HLA-DR, CD86, and PD-L1), and apoptosis (active caspase 3) on monocytes	March 2016	Completed, No Results Posted	Sun Yat-sen University	^[35]
The Efficacy and Safety of Tα1 for Sepsis	NCT02867267	Thymosin Alpha 1	Phase 3 (n = 1106)	Quadruple-blinded, randomized, parallel assignment, placebo-controlled trial	28-day all-cause mortality	September 2016	Completed, No Results Posted	Sun Yat-sem University	^[36]
Effects of shengmai injection combined with thymosin on cellular immune function in patients with sepsis and low immune function: a prospective, randomized, controlled trial	N/A (ChiCTR identifier: ChiCTR2100043911)	Shengmai injection; Thymosin injection	N/A (n = 90)	Parallel assignment, randomized, placebo-controlled trial	Peripheral blood T-cell subsets	January 2019	Completed	The Ninth People’s Hospital of Suzhou	^[37]
Ulinastatin Treatment in Adult Patients with Sepsis and Septic Shock in China	NCT02647554	Ulinastatin	Phase 4 (n = 347)	Quadruple-blinded, randomized, parallel assignment, placebo-controlled trial	28-day all-cause mortality	December 2016	Completed, No Results Posted	Peking Union Medical College Hospital	^[38]
A Study of Nivolumab Safety and Pharmacokinetics in Patients with Severe Sepsis or Septic Shock	NCT02960854	Nivolumab	Phase 1 (n = 38)	Double-blinded, randomized, parallel assignment, placebo-controlled trial	1. Percentage of Incidence Rates of Serious Adverse Events (SAEs), Adverse Events (AEs), Immune-mediated AEs, AEs Leading to Discontinuation, and Deaths 2. Composite of Vital Signs and Electrocardiogram 3. Peak Nivolumab Serum Concentration 4. Trough Nivolumab Serum Concentration 5. Average Nivolumab Serum Concentration 6. Time of Maximum Observed Concentration 7. Area Under the Serum Concentration–time Curve From Time Zero to Time of Last Quantifiable Concentration 8. Total Clearance 9. Volume of Distribution 10. Half-life	December 2016	Completed	Bristol-Myers Squibb	^[39]
Effect of Mesenchymal Stromal Cells on Sepsis and Sepsis and Septic Shock	NCT05283317	Mesenchymal Stem Cells	Phase 1, Phase 2 (n = 30)	Single-blinded, non-randomized, parallel assignment interventional trial	28-day mortality	March 2018	Completed, No Results Posted	TC Enciyes University	^[40]
Randomized, Parallel Group, Placebo Control, Unicentric, Interventional Study to Assess the Effect of Expanded Human Allogeneic Adipose-derived Mesenchymal Adult Stem Cells on the Human Response to Lipopolysaccharide in Human Volunteers	NCT02328612	Intravenous infusion of cells	Phase 1 (n = 32)	Randomized, parallel assignment, open-label trial	Inflammatory response as measured by laboratory measurements and functional assays of innate immunology	October 2014	Completed, No Results Posted	Tigenix S.A.U.	^[41]
Cellular Immunotherapy for Septic Shock: A Phase I Trial	NCT02421484	Allogeneic Mesenchymal Stromal Cells	Phase 1 (n = 9)	Single-group assignment, open-label trial	Number of adverse events as a measure of safety and tolerability	May 2015	Completed, No Results Posted	Ottawa Hospital Research Institute	^[42]
Pharmacokinetics of XueBiJing in Patients with Sepsis	NCT03475732	XueBiJing injection	N/A (n = 35)	Single-group assignment, open-label trial	Plasma concentrations of XueBiJing injection compounds	March 2018	Completed, No Results Posted	Southeast University, China	^[43]
Treatment of Patients with Early Septic Shock and Bio-Adrenomedullin (ADM) Concentration > 70 pg/mL with ADRECIZUMAB	NCT03085758	Adrecizumab	Phase 2 (n = 301)	Double-blinded, randomized, parallel assignment, placebo-controlled trial	1. 90-day mortality 2. Interruption of infusion due to intolerability of adrecizumab 3. Number of participants with treatment-emergent adverse events per treatment group 4. Number of participants with treatment-emergent adverse events per treatment group with mild severity treatment-emergent events 5. Number of participants with treatment-emergent adverse events per treatment group with moderate severity treatment-emergent events 6. Number of participants with treatment-emergent adverse events per treatment group with severe severity treatment-emergent events	December 2017	Completed	Adrenomed AG	^[44]
Effects of Microcirculation of IgGAM in Severe Septic/Septic Shock Patients	NCT02655133	Pentaglobin^®	Phase 2 (n = 20)	Quadruple-blinded, randomized, parallel assignment, placebo-controlled trial	Perfused vessel density (PVD)	January 2016	Completed, No Results Posted	Università Politecnica delle Manche	^[45]
Efficacy of Mw Vaccine in Treatment of Severe Sepsis	NCT02025660	Mw	Phase 2, Phase 3 (n = 50)	Double-blinded, randomized, parallel assignment, placebo-controlled trial	4-week mortality	August 2013	Completed, No Results Posted	Postgraduate Institute of Medical Education and Research	^[46]
Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of 3 Doses of MOTREM in Patients with Septic Shock	NCT03158948	MOTREM: Nangibotide	Phase 2 (n = 50)	Quadruple-blinded, randomized, parallel assignment, placebo-controlled trial	1. Vital signs 2. ECG 3. Number of patients with clinically relevant abnormal laboratory values 4. Presence of anti-LR12 antibodies 5. Adverse events	July 2017	Completed, Results Submitted	Inotrem	^[47]

Table 2. Ongoing interventional studies for the treatment of sepsis and septic shock from the last 10 years.

Title	ClinicalTrials.gov Identifier	Intervention	Phase	Study Design	Primary Outcome	Study Start Date	Study Progress	Primary Sponsor	Ref.
Safety and Efficacy of Interferon-gamma 1β in Patients with Candidemia	NCT04979052	Interferon Gamma-1β	Phase 2 (200 estimated participants)	Randomized, parallel assignment, open-label adaptive trial	Time to first negative blood culture	March 2022	Recruiting	Redboud University Medical Center	^[48]
GM-CSF for Reversal of Immunoparalysis in Pediatric Sepsis-induced MODS Study	NCT03769844	GM-CSF	Phase 4 (120 estimated participants)	Non-randomized, sequential assignment, open-label trial	TNF-α response	December 2018	Active, not recruiting	Nationwide Children’s Hospital	^[49]
GM-CSF for Reversal of Immunoparalysis in Pediatric Sepsis-induced MODS Study 2	NCT05266001	GM-CSF	Phase 3 (400 estimated participants)	Quadruple-blinded, randomized, parallel assignment, placebo-controlled trial	Cumulative 28-day pediatric logistic organ dysfunction (PELOD)-2 score	June 2022	Recruiting	Nationwide Children’s Hospital	^[50]
A prospective, double-blind, randomized controlled trial study of the effect of immune regulation on the prognosis of sepsis	N/A (ChiCTR identifier: ChiCTR2200060069)	Thymopentin	Phase 4 (426 estimated participants)	Double-blinded, randomized, parallel assignment, placebo-controlled trial	28-day mortality rate	June 2022	Not yet recruiting	The First Affiliated Hospital with Nanjing Medical University	^[51]
Application of Immune Cell-oriented Clinical Phenotypic Guides the Treatment of Sepsis	N/A (ChiCTR identifier: ChiCTR2100048326)	Methylprednisolone; Thymosin α1	N/A (200 estimated participants)	Parallel assignment randomized trial (blinding unspecified)	28-day patient mortality rate	July 2021	Not yet recruiting	Renji Hospital, Shanghai Jiaotong University School of Medicine	^[52]
Clinical Efficacy of Ulinastatin for Treatment of Sepsis with Systemic Inflammatory Response Syndrome	NCT05391789	Ulinastatin	Phase 3 (120 estimated participants)	Triple-blinded, randomized, parallel assignment, placebo-controlled trial	ΔSOFA	July 2022	Not yet recruiting	Huashan Hospital	^[53]
Clinical research of fecal microbiota transplantation and probiotics regulating intestinal flora diversity on the systemic immune function in septic patients	N/A (ChiCTR identifier: ChiCTR-INR-17011642)	Fecal microbiota transplantation; Probiotic	N/A (80 estimated participants)	Parallel assignment, randomized trial (blinding unspecified)	1. Gut microbiota composition 2. Immunoglobulin 3. Lymphocyte immune analysis	July 2017	Not yet recruiting	Chinese food fermentation industry research institute	^[54]
Advanced Mesenchymal Enhanced Cell Therapy for Septic Patients	NCT04961658	GEM00220: Enhanced MSCs	Phase 1 (21 estimated participants)	Sequential assignment, non-randomized, open-label, dose-escalation trial	1. Adverse Events 2. Maximum Feasible Tolerated Dose	August 2021	Recruiting	Northern Therapeutics	^[55]
Personalized Immunotherapy in Sepsis	NCT04990232	Anakinra; Recombinant human IFNγ	Phase 2 (280 estimated participants)	Quadruple-blinded, randomized, parallel assignment, double-placebo-controlled trial	Mean total Sequential Organ Failure Assessment score	July 2021	Recruiting	Hellenic Institute for the Study of Sepsis	^[56]
Efficacy and Safety of Therapy with IgM-enriched Immunoglobulin with a Personalized Dose vs. Standard Dose in Patients with Septic Shock	NCT04182737	IgM-enriched polyclonal immunoglobulins	Phase 3 (356 estimated participants)	Single-blinded, randomized, parallel assignment	All-cause, 28-day mortality	May 2020	Recruiting	Massimo Girandis	^[57]
Efficacy, Safety and Tolerability of Nangibotide in Patients with Septic Shock	NCT04055909	Nangibotide	Phase 2 (355 estimated participants)	Quadruple-blinded, randomized, parallel assignment, placebo-controlled trial	Sequential organ failure assessment (SOFA) score	November 2019	Active, not recruiting	Inotrem	^[58]

3. The COVID-19 Example: A Viral Sepsis

Even though the pathogens most frequently implicated in the etiology of sepsis are bacteria (and, to a lesser extent, fungi), sepsis can also occur due to viral infection ^[19]. Undoubtedly, the recent COVID-19 pandemic taught us a lot in this regard. Although most COVID-19 cases were mild or moderate, during the height of the pandemic, 15–20% of patients progressed to severe respiratory infection and adult respiratory distress syndrome (ARDS) ^[19], possibly resulting in septic shock or multiorgan failure ^[59]. Like in traditional sepsis, these patients presented with a dysregulated immune response, with hyperinflammation, activation of the coagulation cascade, and a cytokine storm, as well as lymphocyte exhaustion and the activation of immune checkpoints ^[19]^[59]. Although immune disruption is not as pronounced in COVID-19 as in traditional bacterial sepsis ^[18], the similarities are evident and severe COVID-19 should be regarded as viral sepsis ^[19].

Similarly to traditional sepsis, the host response to COVID-19 is extremely heterogeneous, and different patients might benefit from completely different treatment strategies ^[60]. The determination of disease severity, as well as the identification of immune-stratifying biomarkers, is imperative to adequately guide therapeutic decisions. In the early stages of the disease, eliminating or decreasing viral load is likely to limit the subsequent immune dysregulation, which validates the administration of antiviral agents such as remdesivir ^[60]. A similar approach is followed in bacterial sepsis, where early administration of antibiotics and appropriate source control interventions are key pillars of sepsis management. However, when the disease progresses and patients become critically ill, antimicrobial therapies do not seem to be as effective ^[18]^[61]. Once the immune response becomes unbalanced, immunotherapy comes into play, and patient stratification gains importance.

Changes in biomarkers such as C-reactive protein (CRP), ferritin, and soluble urokinase plasminogen activator receptor (suPAR) indicate worsening inflammation, and the administration of anti-inflammatory therapies should be considered ^[60]. Corticosteroids, for example, have proven to be highly effective at curbing the excessive inflammation in severe disease but would be detrimental to the natural immune response to the virus in earlier stages ^[62]. In addition to corticosteroids, critical COVID-19 patients with high serum levels of IL-6 also benefited from the administration of tocilizumab, a monoclonal antibody that functions as a competitive inhibitor of the IL-6 receptor ^[18]. Anakinra, an IL-1 receptor antagonist, has also been successful in the treatment of COVID-19 patients with lung hyperinflammation and elevated suPAR levels ^[18]^[60], a biomarker that indicates the activation of IL-1 signaling ^[63].

On the other hand, in patients who present with signs of immunoparalysis (illustrated by decreased monocytic HLA-DR, lymphopenia, and the presence of opportunistic infections), immunostimulatory therapies such as IFN-γ or even IL-7 become increasingly valid approaches ^[18]^[60]. Similarly to COVID-19, therapeutic decisions in sepsis should also be grounded in the adequate characterization of the patient’s current immune status.

This entry is adapted from the peer-reviewed paper 10.3390/jcm12082892

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