Supplementary Electronic Material 1 - Immune status

During infection, the innate immune system is in most instances efficient in mounting a protective and balanced response, resulting in elimination of the pathogen. This process is mediated by a variety of pro-inflammatory reactions, such as release of cytokines and chemokines, recruitment and activation of phagocytes to kill pathogens intracellularly and extracellularly (1). The elimination of the pathogenic microorganism is followed by a return to homeostasis via a set of compensatory mechanisms aimed at tempering the initial inflammation and prevention of collateral tissue damage (2). While these finely-tuned processes are generally very effective for host defence, in certain infections the pathogen succeeds to multiply in spite of the immune response, which then becomes unbalanced and harmful to the host. This dysregulated host response might be caused by specific immune defects that result in an inability to clear the pathogen and activate protective host mechanisms, or due to overwhelming inflammatory reactions triggered by certain virulent pathogens. Sepsis is even more complex since both components, namely a ‘loss-of-function’ and an‘over-active’ immune response can co-exist.

In patients with sepsis, several types of immune imbalances are encountered. Initial concepts proposed more than twenty-five years ago proposed that hyperactivation of the immune system, with exaggerated production of cytokines followed by systemic inflammation, is the main pathologic immune response in sepsis (3, 4). Subsequently, more recent studies have also shown that immune defects, especially late in the pathologic process, are prevalent and can contribute to mortality (5, 6). As a consequence, current thinking proposes the departure of immune responses from homeostasis in two opposite directions during sepsis, showing signs of both hyper-inflammation and immune suppression, the extent of which varies between individuals (Figure 2)(7).

Through recognition of pathogen-associated molecular patterns (PAMPs) associated with invading pathogens, and particularly once sepsis is clinically evident, the host response is strongly stimulated to release systemically pro-inflammatory cytokines such as tumour necrosis factor (TNF), interleukin 1 beta (IL-1and interleukin 6 (IL-6). These and other inflammatory mediators released in the bloodstream will induce generalized inflammation, intravascular coagulation, endothelial activation and fluid extravasation, which can result in hypotension, shock, and organ dysfunction (7). The response is further derailed due to the release of damage-associated molecular patterns (DAMPs, or alarmins), host-derived molecules released by injured cells which can activate many of the pattern recognition receptors that also recognize PAMPs, giving rise to a vicious cycle with sustained immune activation and organ dysfunction (8). Patients may deteriorate further to the end of the spectrum in sepsis and develop a state of extreme over-inflammation termed ‘macrophage activation syndrome’-like, which is recognized by fever, low leukocyte counts, liver function abnormalities and very high ferritin concentrations; this is amenable to treatment with anti-cytokine therapies such as recombinant interleukin 1 (IL-1) receptor antagonist (9).

However, due to fast recognition and improved therapeutic and supportive care, fewer sepsis patients die during the first days after ICU admission, but rather develop a critical illness that in addition to persistent inflammation, is also characterized by immunosuppression. The notion that the course of sepsis is now more protracted lasting for days to weeks instead of acute is important for understanding the pathophysiological mechanisms that impact on patient outcome. In sepsis patients with a prolonged clinical course, the disturbances in the host response involve increased lymphocyte apoptosis and lymphopenia, decreased expression of activation markers such as human leukocyte antigen (HLA)-DR on the surface of monocytes, dysregulated cellular metabolism of immune cells, and impaired cytokine production capacity (5, 10-12).

These disturbances in the homeostasis of host defence mechanisms, often a combination of hyper-inflammation and immunosuppression, are main causes of the unfavourable outcome of sepsis due to either hypotension and shock, organ dysfunction, or secondary infections. A precision medicine approach to establish personalized modulator immunotherapy in sepsis is needed in order to identify the precise mechanisms underlying the dysregulated immune response in septic patients, and apply appropriate therapy in an individualized manner.

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