Advances in Sepsis Research – New Tools Against One of the Oldest Diseases?

Currently, sepsis and septic shock with subsequent multi-organ failure are the leading causes of death in adult intensive care units (ICU). Although surgical and pharmacological approaches in sepsis therapy are continuously improving, epidemiological studies show an increased incidence of sepsis over the last 20 years. The high prevalence of sepsis and its high economic impact have led to the development of several projects in the past decades, intended to allow for better recognition and more accurate description of the course of the disease. Sepsis is a complex and life-threatening syndrome induced by a dysregulated host response to infections. For administrative documentation in daily clinical practice of intensivists, patients are often attributed to different morbidities, although they finally die from the sequelae of sepsis, which makes a reliable generation of epidemiologic data from available intra-hospital data files not easy. Thus, outcome data are often resulting from prospective regional cohorts; recent large studies tried to describe epidemiology on a multi-national level. The most affected organs by sepsis and septic shock are the lungs, the cardiovascular system, and the kidneys. With an estimated mortality rate of 40-60%, septic shock is in the focus of adult critical care medicine, and implementation of evidence-based methods and individual, goal-oriented strategies are the key approach against this increasingly prevalent and life-threatening disease. 

Sepsis is one of the oldest described illnesses. The term sepsis was already used by Hippocrates around 400 BC to describe the natural process through which infected wounds become purulent. After this recognition, it took over 2,000 years until the hypothesis was established that it is not the pathogen itself, but rather the host response that is responsible for the symptoms seen in sepsis. In the last 40 years, one major field of sepsis research was the basic cellular and molecular biology to understand the exact mechanisms, why the body sometimes reacts with an overwhelming inflammation to infections, but sometimes not. 

During local infections, a physiologic inflammatory response helps to control the focus, whereas a dysregulated host response leads to macro- and microcirculatory failure, thus inducing organ dysfunction, which determines the symptoms and clinical course of the patients. In other words, in local infections, a normal inflammatory host response controls the focus; a dysregulation of the host response leads to macro- and microcirculatory failure, by which single or multiple organ failure is induced. Hence, inflammation is an essential part of the innate as well as the adaptive immune system. In the initial phase, the inflammation is often a predominantly local syndrome with a more or less pronounced, transient systemic response. On the other hand, this systemic inflammatory response syndrome (SIRS) is potentially harmful, when it is part of a generally overwhelming process. This may lead to circulatory instability by vasodilation due to production of nitric oxide, and to ongoing microcirculatory failure ending with a single or combined organ dysfunction or failure (multiple organ dysfunction syndrome, MODS)

The control of local and systemic pro-inflammatory mechanisms by antiinflammatory counterbalance is an important protective process against further enhancement of inflammation. If, however, the anti-inflammatory reaction gets too strong, this may lead to decreased immune competency with so-called “second hit” infections, for example after major surgery. Thus, the local and systemic imbalance between pro- and anti-inflammation is a crucial aspect of pathogenesis of systemic inflammatory response and multiple organ dysfunctions. This is especially important for patients with sepsis, after multiple traumata, or major surgery, who are often in an immunosuppressive phase, and not only in a phase of uncontrolled hyperinflammation. Components taking part in these pro- and anti-inflammatory processes are found in the innate immune system, mainly as endothelial cells, polymorphonuclear cells (PMN), macrophages etc., as well as in the adaptive immune system, represented by specific humoral B cell and cellular T cell immunity. Additional components are the coagulation as well as the complement system, eicosanoid metabolism, and the endocrine system.

As the mechanisms of inflammatory host response are becoming better defined, interventions aiming to interfere with the host response have been undertaken, largely with disappointing results. Moreover, it was concluded that immunomodulating approaches in septic patients, altogether named as “adjunctive therapy," have to orientate on the patient’s immunologic competence and inflammatory as well as infectious status. Besides low-dose hydrocortisone, and activated protein C, which have been demonstrated to disrupt dysfunctional cascades, thus favourably influencing the course of the disease, the use of intravenous immunoglobulins (ivIG) has been implemented as part of adjunctive therapy. 

A source of infection may result in the release of bacterial toxins like components of the cell wall into the blood stream, and these toxins interact with the cells of the immune system, causing the release of endogenous mediators such as tumour necrosis factor (TNF) or Interleukin1(IL-1), thus causing cardiovascular insufficiency, hypotension, and decreased end-organ perfusion. A large RCT using a monoclonal antibody against the Lipid A fraction of gram negative endotoxin, however, was disappointing, and it was concluded that more investigation is required before these drugs can be used in patients suspected or having gramnegative sepsis. Later, human monoclonal antibodies against specific antigens of bacteria were also tested, but did not result in any benefit for the patients; altogether, the current view on the development of specific monoclonal antibodies against bacterial antigens for treatment of septic patients is rather skeptical. This short list is far away from being complete, and there are many other experimental approaches to inhibit hyperinflammation. However, no other so-called “adjunctive therapy” could reveal sufficient clinical evidence, such as glycaemic control, selenase, specific antibodies, alkaline phosphatase, thiamine, toll-like receptor inhibitors, nitric oxide inhibitors, glutamine, lactoferrin, statins, and many more, which all were tested in clinical trials, but failed to provide any benefit.

In 2017, the results from a large clinical trial were published, presenting data from 149 hospitals including more than 49,000 patients in the USA. It was demonstrated that each hour delay in treating septic patients – measured from the initial time of detecting sepsis – increased mortality by 4% (relative risk). Similar results were found for the single interventions blood culture, antibiotics, and lactate measurement, whereas the effect of early fluid administration was only demonstrated in septic shock patients with a need for vasopressor administration. Hence, it is broadly accepted that intervention in the very early phase of sepsis before the complex inflammatory host response is initiated should be one major option that clinical research should focus on. This latter point supports current discussions that an early fluid challenge might not be favourable in every septic patient (so-called “fluid non-responder”), and that fluid administration should be monitored carefully to avoid a fluid overload with negative effects on the patients’ outcome. A recent approach is to absorb pathogens, i.e. bacteria as well as viruses, with special, heparin-coated cartridges (Seraph™ 100 Microbind™ Affinity Blood Filter, ExThera Medical), which are part of extracorporeal circulation devices – either as a stand-alone haemoperfusion or as part of renal replacement therapy (haemofiltration). There are promising experimental data (MattsbyBaltzer et al, 2011), and first case reports in clinical use are currently published (Seffer et al, 2020). This approach with a more “direct” absorption of pathogens without interfering with the upstream synthesis regulation may be a reasonable alternative to single-hit specific inhibitors, which all keep the risk of a further dysbalance of the immunomodulatory system. A multinational, randomised trial is currently starting to provide the evidence that this new technique is improving the patients’ clinical course.