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Marques, A.; Torre, C.; Pinto, R.; Sepodes, B.; Rocha, J. Treatment Advances in Sepsis and Septic Shock. Encyclopedia. Available online: (accessed on 19 April 2024).
Marques A, Torre C, Pinto R, Sepodes B, Rocha J. Treatment Advances in Sepsis and Septic Shock. Encyclopedia. Available at: Accessed April 19, 2024.
Marques, Adriana, Carla Torre, Rui Pinto, Bruno Sepodes, João Rocha. "Treatment Advances in Sepsis and Septic Shock" Encyclopedia, (accessed April 19, 2024).
Marques, A., Torre, C., Pinto, R., Sepodes, B., & Rocha, J. (2023, May 03). Treatment Advances in Sepsis and Septic Shock. In Encyclopedia.
Marques, Adriana, et al. "Treatment Advances in Sepsis and Septic Shock." Encyclopedia. Web. 03 May, 2023.
Treatment Advances in Sepsis and Septic Shock

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

Title Identifier



Study Design

Primary Outcome

Study Start Date

Study Progress

Primary Sponsor


Safety and Efficacy of Interferon-gamma 1β in Patients with Candidemia


Interferon Gamma-1β

Phase 2

(200 estimated participants)

Randomized, parallel assignment, open-label adaptive trial

Time to first negative blood culture

March 2022


Redboud University Medical Center


GM-CSF for Reversal of Immunoparalysis in Pediatric Sepsis-induced MODS Study



Phase 4

(120 estimated participants)

Non-randomized, sequential assignment, open-label trial

TNF-α response

December 2018

Active, not recruiting

Nationwide Children’s Hospital


GM-CSF for Reversal of Immunoparalysis in Pediatric Sepsis-induced MODS Study 2



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


Nationwide Children’s Hospital


A prospective, double-blind, randomized controlled trial study of the effect of immune regulation on the prognosis of sepsis


(ChiCTR identifier: ChiCTR2200060069)


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


Application of Immune Cell-oriented Clinical Phenotypic Guides the Treatment of Sepsis


(ChiCTR identifier: ChiCTR2100048326)

Methylprednisolone; Thymosin α1


(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


Clinical Efficacy of Ulinastatin for Treatment of Sepsis with Systemic Inflammatory Response Syndrome



Phase 3

(120 estimated participants)

Triple-blinded, randomized, parallel assignment, placebo-controlled trial


July 2022

Not yet recruiting

Huashan Hospital


Clinical research of fecal microbiota transplantation and probiotics regulating intestinal flora diversity on the systemic immune function in septic patients


(ChiCTR identifier: ChiCTR-INR-17011642)

Fecal microbiota transplantation; Probiotic


(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


Advanced Mesenchymal Enhanced Cell Therapy for Septic Patients


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


Northern Therapeutics


Personalized Immunotherapy in Sepsis


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


Hellenic Institute for the Study of Sepsis


Efficacy and Safety of Therapy with IgM-enriched Immunoglobulin with a Personalized Dose vs. Standard Dose in Patients with Septic Shock


IgM-enriched polyclonal immunoglobulins

Phase 3

(356 estimated participants)

Single-blinded, randomized, parallel assignment

All-cause, 28-day mortality

May 2020


Massimo Girandis


Efficacy, Safety and Tolerability of Nangibotide in Patients with Septic Shock



Phase 2

(355 estimated participants)

Quadruple-blinded, randomized, parallel assignment, placebo-controlled trial

Sequential organ failure assessment (SOFA) score

November 2019

Active, not recruiting



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.


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