**5. The treatment of immunoparalysis**

In the last decade, a number of drugs have been developed to restore a normal immune function in patients with solid or hematologic tumors on the basis of many investigations demonstrating the tumor cells are able to suppress in many different ways the host's immune response against themselves. Independently from the substance use and the molecular target, these innovative treatments have been demonstrated to be effective but somehow difficult to handle, as they are associated with a number of side effects ranging from mild to life-threatening [31]. As several similarities exist between tumor- and sepsis-induced blunting of the immune response [32], it is likely that in the next future the immune-boosting treatments will be developed to treat the latter, aiming to develop a precision medicine also in ICU patients [33] (**Table 8**).

Presently, according to the SSC guidelines [2], the immune-targeted approaches are limited to the administration of steroids in not fluid and catecholamine-responding SS, whereas the use of intravenous immunoglobulins (IvIg) is discouraged. Actually, this latter position is questionable as a number of trials performed in several thousands of patients demonstrated that (a) the administration of IvIg is associated with the reduction of mortality in different subsets of SS patients; (b) among the different preparations available, the only ones containing supranormal concentrations of IgM and IgA appears more effective, and (c) the improvement of survival is time-dependent, as a ~6% increase of mortality has been observed for every day of delay in the administration [34].

Besides steroids and IvIg, other treatments aimed to modulate the immune response include blood purification (BPT) techniques and a number of substances able to boost it.


GMC-SF, granulocyte-macrophage colony-stimulating factor; FTL3L, FMS-related tyrosine kinase 3 ligand; PD, programmed death; PDL1, programmed cell death ligand 1; CTL4, cytotoxic T-cell protein 4; TIM3, T-cell immunoglobulin mucin receptor 3; Treg Breg, regulatory T and B cells; TGFβ, transforming growth factor-β; PGE, prostaglandin E2.

**Table 8.** Immunosuppressive pathways shared by cancer and sepsis.

it should be limited to the subjects at risk; as an example, it is worthwhile to monitor the immune function in patients undergoing multiple abdominal surgical procedures for suture

**Figure 2.** The multiple hits phenomenon ultimately leading to the exhaustion of the immune response.

Even with the exclusion of clinical conditions and/or treatments known to cause an immunoparalysis (i.e., solid and hematologic cancers, autoimmune disorders), etc., this circumstance can occur in virtually all ICU patients; however, different studies identified some predisposing factors that should be considered particularly relevant, including septic shock, advanced age, health care-associated infections, elevated Charlson's score indicating a substantial underlying fragility, comorbidities, prolonged hospital and ICU length of stay, and multiple surgical procedures [17, 28, 29]. The latter, which are associated with the repeated activation of the inflammatory and anti-inflammatory responses, according to the multiple hits model, ultimately lead to the exhaustion of the immune response [30]

In the last decade, a number of drugs have been developed to restore a normal immune function in patients with solid or hematologic tumors on the basis of many investigations

dehiscence but not in another one safely recovering after peritonitis.

**4.3. The identification of patients at risk of immunoparalysis**

**5. The treatment of immunoparalysis**

(**Figure 2**).

16 Infectious Process and Sepsis

### **5.1. Blood purification techniques**

Since the 1980s, a number of extracorporeal techniques have been developed aiming to remove the "toxic" mediators responsible for the clinical manifestations of SS.

Independently from their principle of functioning (see later), the BPT consists in an extracorporeal circuit where the patient's blood flows till enters in the depurative device; once the latter is passed, the blood returns to the patient. According to the principle used, the BPT can be subdivided into (a) blood processing or (b) plasma processing techniques. In the former, the whole blood is depurated via a number techniques, which differ in terms of type and surface of the membranes used, their permeability to the high molecular weight of the septic mediators, etc., whereas in the latter the plasma is separated from the blood, processed in a cartridge, and reinfused downstream. The mediators can be eliminated through the membranes or adsorbed over it. In both cases, the neutralizing capabilities are time-limited. A detailed description of the BPT is beyond the aim of this chapter, but some considerations are necessary. First, there are no studies clearly demonstrating the superiority of one of them, even if some meta-analysis indicates that the those using the adsorption are more effective; (b) they can remove also antibiotics, nutrients, vitamins, hormones, etc.; (c) they require anticoagulation; and, most importantly; and (d) they are not selective and thus remove pro- as well as anti-inflammatory mediators [35].

### **5.2. Immune-boosting agents**

Different substances have been used or likely will be used in the next future (**Table 9**) to enhance the depressed immune function in septic and non-septic critically ill patients, including [36, 37]:

• **Interferon-γ** (**IFN-γ**) is a cytokine produced by helper T cell and an activator of monocytes. Different case series and case report performed in a limited number of patients demonstrated that its administration was associated with an increased HLA-DR expression; however, presently there are no RCT fulfilling the EBM criteria demonstrating a beneficial effect on the outcome of patients with SS.

This approach is new as it is aims to increase the immune response to the cancer cells without interfering with their metabolism. Due to their mechanism of action, their administration could determine a potentially life-threatening inflammatory reaction caused by the sudden release of mediators determining a "cytokine storm"; although their use is not codified yet in critically ill septic patients, in a recent RCT, the restoration of the immune response in the absence of a hyperinflammatory reaction was demonstrated in some SS

**Treatment Effect Pro Against**

Removal of mediators Many small RCT

Many small RCT demonstrated their

demonstrated their

Some small RCT and case reports demonstrated its efficacy

Reduced apoptosis " Potentially severe and life-

No EBM-validated Heterogeneity of patients

Immunoparalysis in Septic Shock Patients http://dx.doi.org/10.5772/intechopen.88866 19

Heterogeneity of techniques (i.e., HVHV vs. plasma

Heterogeneity of patients

Need of anticoagulation

Possible septic shock-like Systemic inflammatory

Systemic inflammatory

Systemic inflammatory

threatening side effects

treated High costs

Not selective

adsorption)

Not selective

reactions

reactions

reactions

High costs No RCT available

" Possible septic shock-like

" Possible septic shock-like

treated

efficacy

efficacy

↓ TNF and other proinflammatory mediators

of pro-inflammatory

of pro-inflammatory

Interferon-γ Enhanced production

GMC-SF Enhanced production of immune cells

IL-7 Enhanced production

mediators

mediators

Available IvIg Antibacterial action

Blood purification techniques

Immune checkpoint inhibitors

Not yet available

Independently from its source, septic shock can be considered a double-step process: the initial phase is characterized by an intense inflammatory response that is counterbalanced

patients given a novel PD1i at different doses [38].

**Table 9.** Possible immunomodulating treatments in septic shock.

**6. Conclusions**



**Table 9.** Possible immunomodulating treatments in septic shock.

This approach is new as it is aims to increase the immune response to the cancer cells without interfering with their metabolism. Due to their mechanism of action, their administration could determine a potentially life-threatening inflammatory reaction caused by the sudden release of mediators determining a "cytokine storm"; although their use is not codified yet in critically ill septic patients, in a recent RCT, the restoration of the immune response in the absence of a hyperinflammatory reaction was demonstrated in some SS patients given a novel PD1i at different doses [38].

### **6. Conclusions**

**5.1. Blood purification techniques**

18 Infectious Process and Sepsis

as anti-inflammatory mediators [35].

on the outcome of patients with SS.

decreased HLA-DR expression.

patients suffering from immunoparalysis.

**5.2. Immune-boosting agents**

ing [36, 37]:

Since the 1980s, a number of extracorporeal techniques have been developed aiming to

Independently from their principle of functioning (see later), the BPT consists in an extracorporeal circuit where the patient's blood flows till enters in the depurative device; once the latter is passed, the blood returns to the patient. According to the principle used, the BPT can be subdivided into (a) blood processing or (b) plasma processing techniques. In the former, the whole blood is depurated via a number techniques, which differ in terms of type and surface of the membranes used, their permeability to the high molecular weight of the septic mediators, etc., whereas in the latter the plasma is separated from the blood, processed in a cartridge, and reinfused downstream. The mediators can be eliminated through the membranes or adsorbed over it. In both cases, the neutralizing capabilities are time-limited. A detailed description of the BPT is beyond the aim of this chapter, but some considerations are necessary. First, there are no studies clearly demonstrating the superiority of one of them, even if some meta-analysis indicates that the those using the adsorption are more effective; (b) they can remove also antibiotics, nutrients, vitamins, hormones, etc.; (c) they require anticoagulation; and, most importantly; and (d) they are not selective and thus remove pro- as well

Different substances have been used or likely will be used in the next future (**Table 9**) to enhance the depressed immune function in septic and non-septic critically ill patients, includ-

• **Interferon-γ** (**IFN-γ**) is a cytokine produced by helper T cell and an activator of monocytes. Different case series and case report performed in a limited number of patients demonstrated that its administration was associated with an increased HLA-DR expression; however, presently there are no RCT fulfilling the EBM criteria demonstrating a beneficial effect

• **Granulocyte-macrophage colony-stimulating factor** (**GMC-SF**) stimulates the production of neutrophils from the bone marrow. Even if prophylactic use in neutropenic patients did not demonstrate any beneficial effect, a number of investigations demonstrated that its administration was associated with an improved outcome especially in patients with a

• **Interleukin-7** (**IL-7**) is a cytokine released by bone marrow and thymus cells that prompts the growth and the differentiation of T cells. This substance is considered an immuneboosting agent in patients with cancer and multifocal leukoencephalopathy and in septic

• **Programmed death inhibitors** (**PD1i**) are proteins whose effect is to block the programmed death of immune cells, which appears to be a critical factor for the progression of cancer.

remove the "toxic" mediators responsible for the clinical manifestations of SS.

Independently from its source, septic shock can be considered a double-step process: the initial phase is characterized by an intense inflammatory response that is counterbalanced by the production of several anti-inflammatory substances aiming to restore the immunity pre-sepsis steady state. However, in many cases this compensatory mechanism prevails and not only extinguishes the initial response but determines a condition of immunoparalysis that dominates the clinical course and influences the outcome. Unfortunately, the current approach is mainly directed against the initial inflammatory phase although some techniques of monitoring of the immune function are currently developed and others are being studied. The same concepts apply to treatments directed to potentiate the immune capabilities, but in this case the goal appears to be still far.

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DOI: 10.1186/cc10457
