Sepsis therapies: learning from 30 years of failure of translational research to propose new leads

Abstract

Sepsis has been identified by the World Health Organization (WHO) as a global health priority. There has been a tremendous effort to decipher underlying mechanisms responsible for organ failure and death, and to develop new treatments. Despite saving thousands of animals over the last three decades in multiple preclinical studies, no new effective drug has emerged that has clearly improved patient outcomes. In the present review, we analyze the reasons for this failure, focusing on the inclusion of inappropriate patients and the use of irrelevant animal models. We advocate against repeating the same mistakes and propose changes to the research paradigm. We discuss the long-term consequences of surviving sepsis and, finally, list some putative approaches-both old and new-that could help save lives and improve survivorship.

Keywords: animal models; cytokine storm; personalized medicine; reprogramming; sepsis.

Figure 1. Summary of sepsis pathophysiology

Upon direct activation of immune and endothelial cells by the pathogen‐associated molecular patterns, there is a massive release of inflammatory mediators which affect each body system. Inflammatory response activates the central nervous system, which acts by cholinergic anti‐inflammatory impulsion and altered neuroendocrine response to control the body response to infection and increase chances of survival. Cardiovascular dysfunction plays a central role in the pathogenesis of sepsis with the major role of vasoplegia, hypovolemia, microcirculation perturbations, and cardiomyopathy. Altered endothelium and inflammatory cells lead to the development of acute respiratory distress syndrome (ARDS). The direct action of cytokines and toxins, together with decreased blood flow, leads to acute kidney injury (AKI). Inflammatory response and ischemia alter gut permeability which enables entry of bacteria and their metabolites into the tissues. Both bacterial products and inflammatory mediators affect bone marrow progenitor cells enhancing the emergency myelopoiesis. Most often, the failure of multiple organs is present, which has significant consequences as there is a cross‐talk between injured organs which further perpetuates their dysfunction. For a more detailed perspective on organ failure in sepsis, we refer to a recent review (Lelubre & Vincent, 2018).

Figure 2. Summary of the players and pathophysiological events occurring and influencing sepsis

Complex interactions between genetic and chronic health status determine the host response to pathogens. The magnitude and variety of humoral and cellular response may lead to organ dysfunctions, which are a key denominator of sepsis in comparison with other forms of infection.

Figure 3. Compartment‐specific reprogramming of the macrophages in sepsis

Microenvironment modulates the response of macrophages during sepsis. Therefore, the features of cells from one compartment cannot be generalized upon others.

Figure 4. Long‐term sequel of sepsis

Most of the sepsis cases occur in patients with chronic comorbidities. Within days to weeks, some patients can be healed while some will succumb due to acute organ dysfunctions. However, a high frequency of patients develop chronic critical illness (ICU stay for more than 14 days). This condition is caused mechanistically by the persistent inflammation, immunosuppression, and catabolism syndrome (PICS). During this phase, some patients die due to organ dysfunctions, and some develop secondary infections. A group of chronic critical illness patients still can fully recover. However, most of the patients will experience the worsening of their chronic conditions and suffer from the onset of new ones.

Figure 5. Some keys differences in murine and human physiology that affect the response to sepsis (CRP —C‐reactive protein, MAC—membrane attack complex, SAP—serum amyloid protein)

Figure 6. Strategies to enrich treatment‐sensitive subpopulations of patients

At the admission, patient is subjected to supportive therapies and samples are taken for laboratory analyses. The flowchart on the left side shows current approach to stratify the patients using relatively simple methods such as clinical scales, mediator concentrations, or activation of immune cells. Then basing on the thresholds patients are qualified or not to a given specific therapy. This approach is already used in some clinical trials and for some biomarkers feasible at the bedside. On the right, a procedure of future individual medicine is presented. It involves a more complicated approach which applies potent analytical platforms to assess the genome, transcriptome, proteinome, and metabolome of the patient. Together with metagenome of the pathogen, the decision is made on the drug to prescribe as well as its dose and timing.