**2. Pathophysiology of septic shock: a classical overview**

### **2.1. The inflammatory response**

both the description and the therapies apply to acutely ill patients suffering from an infectioninduced overwhelming reaction determined by a huge number of pro-inflammatory mediators produced and released by the innate immunity system. However, more than 20 years ago, Bone [3] hypothesized that this early hyperinflammatory phase could be accompanied by a compensatory anti-inflammatory response (CARS) aiming to limit the tissue damage. In the last decade, the concept of CARS has changed from a time-limited and somehow beneficial mechanism to a harmful reaction, potentially leading to a condition of marked reduction of the immune capabilities known as immunoparalysis [4–6]. Clinically, this condition is marked by recurrent and/or unresolving infections caused by germs with relatively low virulence; the reactivation of silent virus such as *cytomegalovirus* (CMV), Epstein-Barr virus (EBV), and herpesvirus (HV); a persisting low-grade inflammation; nutrition-resistant hypercatabolism; and muscle wasting [7, 8] (**Table 1**). The immunoparalysis characterizes also the clinical course of the chronic critically ill patients, namely, subjects who survived the initial insult (i.e., septic shock due to pneumonia, peritonitis, etc.) but fails to recover enough to be weaned from the mechanical ventilation and discharged from the intensive care unit (ICU) [9]. Moreover it should be noted that factors other than pathophysiological mechanisms can reduce the immune response, including the administration of steroids and norepinephrine [1, 10]. The aims of this chapter are (1) to review the main mechanism determining a SS, (2) to describe the transition from an easily recognizable hyperinflammatory condition to a less straightforward diagnosable one featured by a downregulation of the immune capabilities, (3) to provide some monitoring tools of the immune function, and, finally, (4) to identify some

possible therapeutic approaches.

8 Infectious Process and Sepsis

Comorbidities Often absent

Laboratory findings ↑↑ or ↓ neutrophil count,

Clinical course Resolution of sepsis

LOS, length of stay.

**Variable Uncontrolled inflammatory response Immunoparalysis**

Patients population Young, middle-aged Elderly, fragile

output, rapidly evolving MODS, community

Germs characteristics Virulent, toxin releasing Low virulence, opportunistic

Nutritional status Normal Sarcopenia/cachexia

**Table 1.** Different clinical presentations of sepsis-induced immunological alterations.

Altered mental status, normo-/hypothermia, slow-evolving MODS, health care- or hospital-

acquired infections

High Charlson's index

Latent virus reactivation

Often present

↓ lymphocyte

Muscle wasting

Late deaths

Protracted ICU LOS Chronic critical disease

Clinical phenotype Fever, arterial hypotension, elevated cardiac

or surgical infections

Low Charlson's index

↑ blood lactate levels

Immunorestoration Early deaths

Since the late 1970s, it has become clear that the clinical and biochemical manifestations of sepsis and its related complications are not caused directly by invading germ(s) but rather by the host's response to the infection. The innate immune response largely accounts for the above described signs and symptoms. The presence of microorganism-derived substances collectively known as pathogen-associated molecular pattern (PAMP) which include endotoxin, capsular antigens, elements derived from the cell wall, flagellins, and other substances derived from the bacterial lysis determines the rapid activation of genes encoding for an extremely elevated (and still partially unknown) mediators able to trigger a strong inflammatory reaction, including the tumor necrosis factor-α (TNF), a number of interleukins (IL), the platelet-activating factor (PAF), etc. (**Table 2**). It is worthwhile to recall that (a) the list of mediators is incomplete because new elements are added on a weekly or at maximum monthly basis, (b) the rise of blood levels of inflammatory mediators is a matter of minutes since it represents the first line of defense to contrast the deleterious effects of PAMP and DAMPS, and (c) for this reason, the innate response is highly similar among all species of mammalians [6].

Independently from their biochemical structure, the term inflammasome lumps together all these heterogeneous mediators that are characterized by (a) the presence of many positive and negative feedback loops, determining an array that can be better conceived as a network


**Table 2.** Some relevant pro-inflammatory mediators.

and not a cascade, thus making understandable the therapeutic failure demonstrated in many trials in which septic patients were treated with substances aimed to the block a single mediator via monoclonal or chimeric specific antibodies (Ab) such as anti-TNFαAb or with the administration of circulating antagonists (ra) (i.e., soluble IL1-ra and TNF TNFα-ra) directed to block the receptors present on the cell surface; (b) the pleiotropic and paracrine effects, accounting for the multiple effects exerted in different organs; (c) the interference with the mitochondria causing a disturbance of the O<sup>2</sup> uptake and consumption by the tissues; and (d) the interaction with other biological systems including the complement system and the coagulative cascade. Notably, the very same mediators are produced in noninfectious conditions, including trauma, low-flow states, surgery, burns, etc.; in these circumstances the trigger is represented by an intracellular substance derived from the injured tissues (DAMP, damage-associated molecular patterns). The endothelium is massively involved in this reaction causing a microvascular plugging and the abnormal production of nitric oxide (NO) which exert a profound vasodilation [11, 12].

From an evolutionary perspective, it is likely that these mediators have been developed and maintained, aiming to contain the initial inoculum and to destroy the responsible organisms. This explains why in most cases an infection does not cause a SS: actually, the latter occurs only when the pro-inflammatory mediators exert their effects at a systemic level, thus determining the clinical phenotype of SS and the almost unavoidable presence of the simultaneous dysfunction of different organs and systems even not directly involved by the infection (MODS).

### **2.2. The compensatory reaction**

The secretion of inflammasome is accompanied by the production of other substances aimed to limit their action at a local level and, at the same time, to prevent their systemic spread (**Table 3**). As stated above for the inflammatory mediators, their list is incomplete for the very same reasons. Actually, it was hypothesized that during the initial phase (almost), only proinflammatory mediators were produced and that these conditions subsided due to the action of the CARS-associated mediators. Despite its popularity, it became clear that this scheme represents an oversimplification as (a) both classes of substances are produced since the initial phase of sepsis albeit in different rates; (b) the action of anti-inflammatory mediators is responsible for the late-onset immunoparalysis; and finally (c) a low-level production of pro-inflammatory substances can be maintained even during the advanced stages of sepsis leading to malnutrition, protein waste, and reduced adaptive immunity. Overall, the sepsisassociated immunoparalysis resembles the normal aging process of the immune system (immunosenescence) that is characterized by the overall downregulation of both the innate and adaptive immunity functions. This appears particularly relevant as the ever-increasing age of septic patients exposes them to both conditions.

Put shortly, it appears that the mediators implicated in the CARS can represent a doubleedged sword, as they both can exert (a) a beneficial role when they determine the restoration of the immune condition existing prior to the sepsis (immune restoration) and (b) can trigger a life-threatening condition when their excess production and/or duration of action causes the shutdown of the immune response [13, 14].

In conclusion, (at least) three clinical trajectories can be hypothesized (**Figure 1**): the first includes patients with an intense hyperinflammatory reaction that subsides once the CARS is well established and the immune function is restored; in the second the initial phase is shorter and weaker, and the CARS determines a short-lived immunoparalysis preceding the return

**Figure 1.** Possible clinical trajectories of patients with sepsis shock. Line 1, intense hyperinflammatory reaction followed by CARS and the return to the baseline immune state. Line 2, weak hyperinflammatory reaction followed by immunoparalysis and immune restoration. Line 3, immunoparalysis not preceded by a hyperinflammatory reaction.

**Cytokine Source Effects Interactions**

phagocytosis

Immunosuppression

Inhibition of antigen presentation and

Immunosuppression "

Promotes Th2 T-cell differentiation Induces the production of IL-10

Suppression of the production of inflammatory mediators

Immunoparalysis in Septic Shock Patients http://dx.doi.org/10.5772/intechopen.88866 11

IL-10 Innate and adaptive immune system

> Th2 T cells Basophils Eosinophils

TGF, transforming growth factor.

Smooth muscle cells

**Table 3.** Some relevant anti-inflammatory mediators.

TGF-β Macrophages

IL-4 Mast cells


**Table 3.** Some relevant anti-inflammatory mediators.

and not a cascade, thus making understandable the therapeutic failure demonstrated in many trials in which septic patients were treated with substances aimed to the block a single mediator via monoclonal or chimeric specific antibodies (Ab) such as anti-TNFαAb or with the administration of circulating antagonists (ra) (i.e., soluble IL1-ra and TNF TNFα-ra) directed to block the receptors present on the cell surface; (b) the pleiotropic and paracrine effects, accounting for the multiple effects exerted in different organs; (c) the interference with the

(d) the interaction with other biological systems including the complement system and the coagulative cascade. Notably, the very same mediators are produced in noninfectious conditions, including trauma, low-flow states, surgery, burns, etc.; in these circumstances the trigger is represented by an intracellular substance derived from the injured tissues (DAMP, damage-associated molecular patterns). The endothelium is massively involved in this reaction causing a microvascular plugging and the abnormal production of nitric oxide (NO)

From an evolutionary perspective, it is likely that these mediators have been developed and maintained, aiming to contain the initial inoculum and to destroy the responsible organisms. This explains why in most cases an infection does not cause a SS: actually, the latter occurs only when the pro-inflammatory mediators exert their effects at a systemic level, thus determining the clinical phenotype of SS and the almost unavoidable presence of the simultaneous dysfunction of different organs and systems even not directly involved by the infection (MODS).

The secretion of inflammasome is accompanied by the production of other substances aimed to limit their action at a local level and, at the same time, to prevent their systemic spread (**Table 3**). As stated above for the inflammatory mediators, their list is incomplete for the very same reasons. Actually, it was hypothesized that during the initial phase (almost), only proinflammatory mediators were produced and that these conditions subsided due to the action of the CARS-associated mediators. Despite its popularity, it became clear that this scheme represents an oversimplification as (a) both classes of substances are produced since the initial phase of sepsis albeit in different rates; (b) the action of anti-inflammatory mediators is responsible for the late-onset immunoparalysis; and finally (c) a low-level production of pro-inflammatory substances can be maintained even during the advanced stages of sepsis leading to malnutrition, protein waste, and reduced adaptive immunity. Overall, the sepsisassociated immunoparalysis resembles the normal aging process of the immune system (immunosenescence) that is characterized by the overall downregulation of both the innate and adaptive immunity functions. This appears particularly relevant as the ever-increasing

Put shortly, it appears that the mediators implicated in the CARS can represent a doubleedged sword, as they both can exert (a) a beneficial role when they determine the restoration of the immune condition existing prior to the sepsis (immune restoration) and (b) can trigger a life-threatening condition when their excess production and/or duration of action causes the

uptake and consumption by the tissues; and

mitochondria causing a disturbance of the O<sup>2</sup>

10 Infectious Process and Sepsis

which exert a profound vasodilation [11, 12].

age of septic patients exposes them to both conditions.

shutdown of the immune response [13, 14].

**2.2. The compensatory reaction**

**Figure 1.** Possible clinical trajectories of patients with sepsis shock. Line 1, intense hyperinflammatory reaction followed by CARS and the return to the baseline immune state. Line 2, weak hyperinflammatory reaction followed by immunoparalysis and immune restoration. Line 3, immunoparalysis not preceded by a hyperinflammatory reaction.

In conclusion, (at least) three clinical trajectories can be hypothesized (**Figure 1**): the first includes patients with an intense hyperinflammatory reaction that subsides once the CARS is well established and the immune function is restored; in the second the initial phase is shorter and weaker, and the CARS determines a short-lived immunoparalysis preceding the return toward the baseline immune function; and in the third one, the CARS prevails and causes the loss of the immune capabilities.
