Advances and Challenges in Sepsis Management: Modern Tools and Future Directions

Santacroce E, D'Angerio M, Ciobanu AL, Masini L, Lo Tartaro D, Coloretti I, Busani S, Rubio I, Meschiari M, Franceschini E, Mussini C, Girardis M, Gibellini L, Cossarizza A, De Biasi S. Advances and Challenges in Sepsis Management: Modern Tools and Future Directions. Cells. 2024 Mar 2;13(5):439. doi: 10.3390/cells13050439. PMID: 38474403; PMCID: PMC10931424.

Abstract

Sepsis, a critical condition marked by systemic inflammation, profoundly impacts innate and adaptive immunity, often resulting in lymphopenia. This immune alteration spares regulatory T cells (Tregs) but significantly affects other lymphocyte subsets, leading to diminished effector functions, altered cytokine profiles, and metabolic changes. The complexity of sepsis stems from its pathophysiology and the heterogeneity of patient responses, posing significant challenges in developing universally effective therapies. This review emphasizes the importance of phenotyping in sepsis to enhance patient-specific diagnostic and therapeutic strategies. Flow cytometry emerges as a crucial tool, offering rapid, low-cost, and detailed analysis of immune cell populations and their functional states. This technology facilitates understanding immune dysfunctions in sepsis and identifying novel biomarkers. Integrating flow cytometry with omics data, machine learning, and clinical observations could refine sepsis management, highlighting the shift towards personalized medicine in critical care.

Introduction

As critical care medicine evolves, significant updates in understanding and managing sepsis have emerged. The 2023 guidelines redefine sepsis as “life-threatening organ dysfunction resulting from a dysregulated host response to infection,” emphasizing its severity and potential lethality. Despite advances in treatment, sepsis remains a formidable challenge with high in-hospital mortality rates, contributing to about 20% of global mortality. Clinical symptoms include changes in body temperature, leukocytosis or leukopenia, tachycardia, hypotension, and hyperventilation. However, these symptoms may also originate from non-infectious sources, necessitating markers for early detection of sepsis and organ dysfunction, allowing for early and targeted interventions.

Sepsis Pathophysiology: A Multi-Level Perspective

Sepsis involves complex molecular, cellular, and organ system interactions. Central to its pathogenesis is the interplay between the immune system and pathogens. The immune response, initially protective, can become unbalanced, leading to excessive inflammation and tissue injury. The gut microbiome undergoes significant disruption in sepsis, marked by decreased microbial diversity and overgrowth of opportunistic pathogens, affecting systemic immunity.

Patients with sepsis often exhibit concurrent hyperinflammation and immune suppression, resulting in variable clinical outcomes, including persistent inflammation, immunosuppression, and catabolism syndrome (PICS) in critically ill patients. The proinflammatory phase in sepsis is characterized by intense systemic release of cytokines and other inflammatory mediators, leading to tissue damage and organ dysfunction. Neutrophils play a vital role in this phase, contributing to hyperinflammation through the release of proteases and reactive oxygen species and forming neutrophil extracellular traps (NETs).

Inflammasomes, high molecular weight protein complexes, play a crucial role in sepsis by activating inflammatory caspases and cytokines of the IL-1 family. The anti-inflammatory phase involves the suppression of various immune cells, including T cells and B cells, their exhaustion, and reprogramming through epigenetic changes.

Sepsis Pathophysiology across Organ Systems

Sepsis affects various organ systems, including the cardiovascular system, which undergoes significant changes during progression from localized infection to severe systemic inflammation and septic shock. Despite normal or increased cardiac output, patients with sepsis often experience acute biventricular dysfunction and elevated lactate levels, indicating a critical imbalance in tissue oxygenation and metabolic dysfunction. Sepsis induces profound alterations at the endothelial level, such as increased leukocyte adhesion, a shift to a procoagulant state, and compromised barrier function, leading to tissue edema and microvascular disturbances. In the liver, sepsis impairs crucial functions, intensifying systemic inflammation. Septic acute kidney injury (AKI) involves cytokine and immune-mediated microvascular and tubular dysfunction.

Biomarkers in Sepsis

The complexity of sepsis and limitations of current treatments require innovative approaches. Enhancing immune competence could be pivotal in resolving primary infections and preventing fatal secondary complications. The immune response in sepsis varies, depending on individual variables such as age, cytokine profiles, immune competence, and comorbidities. Understanding the patient’s phenotype is crucial in developing a tailored therapeutic approach, considering both the disease phase and individual patient factors. The diversity of sepsis complicates the identification of high-risk patients, early diagnosis, and disease-specific treatments. Delays in appropriate treatment, especially in administering potent antibiotic regimens, substantially increase mortality risk.

Flow cytometry, a powerful technology for detecting and monitoring multiple markers at the cellular level, is effective for assessing cell heterogeneity and is a quicker, less expensive method for studying immune cells. This technique, known as immunophenotyping, is pivotal in understanding the roles of innate and adaptive immune cells in sepsis.

Immune Cells Alterations

Sepsis affects various immune cells, including neutrophils, monocytes, NK cells, γδ T cells, MAIT cells, T lymphocytes, and B lymphocytes. These alterations, including delayed apoptosis, reduced ROS production, impaired functionality, and phenotypic changes, contribute to immune dysfunction observed in sepsis patients. Neutrophils exhibit delayed apoptosis, persistent dysfunction, and increased IL-10 production. Monocytes show impaired functionality, reduced HLA-DR expression, and increased PD-L1 expression. NK cells experience increased apoptosis, reduced cytokine secretion, and impaired cytotoxic function. γδ T cells and MAIT cells exhibit reduced effector functions and increased apoptosis. T lymphocytes, particularly CD4+ T cells, are significantly reduced due to apoptosis and exhibit impaired function. B lymphocytes show reduced proliferation, antibody secretion, and increased apoptosis.

Metabolic Shifts in Immune Cells

Metabolic shifts in immune cells during sepsis involve changes in energy production pathways. Sepsis initially induces a hypermetabolic state, followed by a hypometabolic state, characterized by reduced oxidative phosphorylation and increased glycolysis. This transition forms the basis of the “hibernation theory,” a protective mechanism allowing cellular recovery. Sepsis-induced mitochondrial damage is the main cause of metabolic disorders in septic patients. Glycolysis leads to the production of pro-inflammatory factors, causing “inflammatory storms” and subsequent cellular damage. The shift from glucose to fatty acid oxidation is marked by increased levels of fatty acid transporters and associated with an anti-inflammatory phenotype.

Sepsis Therapy: Phenotyping and Personalized Approaches

Sepsis presents significant challenges in diagnosis and treatment due to its heterogeneity. The concept of precision medicine is gaining traction, focusing on tailored strategies based on individual patient characteristics. This approach is crucial given the varied manifestations of sepsis and the need to determine effective treatment strategies for different patient subgroups. Flow cytometry, omics data, and machine learning are crucial in refining sepsis management by providing valuable insights into immune dysfunctions and aiding in identifying novel biomarkers. Advanced machine learning techniques and multi-omics datasets can improve patient stratification and guide personalized treatment approaches.

Omics Technologies

The evolving field of “omics” (genomics, transcriptomics, proteomics, metabolomics, cytomics) offers systems-biology-based approaches for developing new diagnostic tools in sepsis. Phenotyping can categorize patients into subgroups of a clinical syndrome or disease, defined by a shared feature, while endotyping goes further, categorizing patients into subtypes associated with specific pathobiological or functional mechanisms. Flow cytometry emerges as a crucial tool in sepsis research, enabling rapid and precise immunophenotyping. Advanced machine learning techniques integrated with multi-omics datasets offer substantial progress in sepsis research, identifying novel biomarkers and immune profiles critical for early diagnosis and personalized therapeutic strategies.

Future Directions

While omics technologies herald a new era of precision medicine in sepsis care, the immediate need for practical diagnostic and therapeutic tools in clinical settings is pressing. Integrating advanced machine learning techniques with multi-omics datasets offers substantial progress in sepsis research, identifying novel biomarkers and immune profiles critical for early diagnosis and personalized therapeutic strategies. The synergy of omics data and machine learning opens new perspectives in sepsis, supporting better characterization of patient phenotypes and promoting tailored approaches to treatment.

Conclusion

The management of sepsis remains a significant challenge due to its complexity and the heterogeneity of patient responses. Understanding the molecular, cellular, and organ system interactions in sepsis is crucial for developing effective diagnostic and therapeutic strategies. Phenotyping and personalized approaches, supported by advanced technologies like flow cytometry, omics data, and machine learning, are essential in refining sepsis management. This shift towards personalized medicine holds promise for more precise interventions, improving outcomes for sepsis patients.

Watch this video on "Detecting Sepsis in the Ventilated Patient (Session 6 | 2024 WSC Spotlight)

ACCESS FULL ARTICLE HERE

Discussion Questions

1. How can the integration of flow cytometry, omics data, and machine learning enhance personalized medicine in sepsis management?
2. What are the challenges and benefits of implementing precision medicine in the treatment of sepsis?
3. How do metabolic shifts in immune cells during sepsis contribute to the pathophysiology of the condition, and what implications does this have for therapeutic strategies?

Javier Amador-Casta?eda, BHS, RRT, FCCM

Interprofessional Critical Care Network (ICCN)

[email protected]

YouTube Channel

Customer Service Line