Which Among Septic Patients Are the Best Candidate for Immunoglobulins?



Fig. 3.1
Different molecules of Ig



The G class is considered prototypical and is formed by two heavy chains (H) with variable weight between 50 and 70 kDa and two light chains (L) weighing around 20–25 kDa (Fig. 3.2). Electrostatic bonds and bisulphurate bridges keep the single chains together.

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Fig. 3.2
Schematic two-dimensional structure of an IgG molecule. VH and VL indicate the variable regions of the heavy and light chains, respectively. The different epitopes are recognized by the variable regions located on both the light and heavy chains (Fab region). The CDR segments are hypervariable domains located in the Fab regions, which are separated from each other by relatively constant polypeptide chains. The Fc region binds to the complement and to the receptors located on the surface of the RES cells and triggers their activation

Both chains have a variable (V) region which interacts with the antigen and a constant one (C) which activates the immune system functions like the complement system, the phagocytosis, the cell’s mediated lysis, etc.

The interconnection region between V and C components undergoes three-dimensional arrangements in order to adapt its structure to the Ag surface. Each variable region is formed by other three hypervariable subregions where their shape defines the specificity of the molecule. Both variable and fixed regions on the chains L and H are arranged on of Fab region, which binds the Ag.

In general terms, the Ig molecules can be considered biochemical transducers able to (Table 3.1):


Table 3.1
Mechanisms of action of immunoglobulins



































Toxin inactivation

Neutralization of endotoxin and exotoxins

Increase clearance of endotoxin

Reduction of bacterial cell adherence, invasion, and migration

Stimulation of the leukocyte and serum bactericidal action

Enhancement of endotoxin-induced neutrophilic oxidative burst (7S-IvIgG); intact

Reduction of endotoxin-induced neutrophilic oxidative burst (5S-IvIgG; F(ab′)2 fragments and IgM)

Enhancement of serum opsonic activity

Modulation of cytokine effect

Modulation of the release of cytokine and their antagonists

 ↓ Proinflammatory mediators

 ↑ Anti-inflammatory mediators

Infusion of cytokines and antagonists contained in the Ig preparations

Cytokine neutralization by anti-cytokine antibodies

Modulation of the complement cascade




  • Recognize and neutralize infective germs and their derived substances


  • Opsonize extraneous molecules in order to facilitate their elimination by the reticulum-endothelial system


  • Recognize and inhibit early and late-released sepsis mediators, by a direct effect on the cell nucleus which produces and facilitates their scavenging by the SREs


  • Activate the complement system


  • Influence the death of the immunitary cells via apoptotoc and non-apoptotic pathways

Then, it appears that the Ig can modulate the inflammatory response, and this capability can be useful in the different phases of sepsis, which are characterized by a different arrangement of the immune response. Actually, sepsis and its related conditions as severe sepsis and septic shock can be considered as a complex and articulated response to an infection, which is characterized by (at least) two different phases. In the first one, whose features are the classical signs of fever, leucocytosis, hemodynamic instability, metabolic acidosis, etc., there is a predominant secretion of proinflammatory mediators (TNF, various interleukins, etc.) that can cause the derangement of organs different from the one in which the infective process and immunity response have started. This reaction is mainly determined by the action of the indicated proinflammatory mediators, whose qualitative and quantitative properties are genetically determined and thus vary from an individual to another; the subsiding of this initial response is determined either by reduction of the production of proinflammatory substances and by the contemporaneal release of mediators with anti-inflammatory capabilities [3].

If the patient survive the initial insult, a second phase ensues, which is characterized by the reduction and progressive disappearance of the above described proinflammatory response due to the overwhelming action of anti-inflammatory mediators ultimately leading to a state of immunoparalysis; this condition is characterized by a profound alteration of both natural and adaptive immunity mechanism, and the consequent immunitary state can be compared to that present in advanced neoplastic conditions [4, 5]. This state, which is difficult to diagnose due to the lack of suitable biological markers, is particularly frequent in patients affected by multiple chronic conditions, who can survive the infection and/or its related conditions causing the intensive care unit admission (surgery, lung infection, etc.) but who cannot be weaned from the mechanical ventilation and are prone to multiple infections, thus becoming critically ill chronic patients.

The above described clinical aspects can justify the use of IvIg both in the early phase of sepsis, in which they can modulate an excessive systemic inflammatory response, and in the more advanced phase, during which their antibacterial action can restore the adaptive immune response. These actions are only partly shared by other immunomodulatory substances recommended by the SSC guidelines, like steroids with glucocorticoid activity: indeed, if their use has a rationale in the early inflammatory phase, in the later one, their use can contribute at the occurrence of immunoparalysis. Anyhow, the use of IvIg does not replace the other therapies indicated by the SSC, including the early administration of appropriate antibiotics and the surgical drainage of infective sources. Even if it is probable that in the next future some other immunomodulatory and immunostimolatory molecules can be introduced in clinical practice, actually their application has to be considered only experimental.



3.3 The Administration of IvIg in Sepsis


Although the IvIg use has long anticipated the first edition of the SSC, their administration in septic patients has been initiated long before and was based for long time more on the intuition of their utility than on robust scientific bases. In general, the different IvIg preparation currently used in clinical practice can be divided into two principal categories. The first one is formed by monoclonal antibodies directed versus one single antigen (e.g., the antitetanic toxin Ig), and the other is compounded by polyclonal antibodies directed against different antigens.

On the other hand, the application’s modality in the sepsis treatment is based essentially on two different strategies [6]:

(a)

The administration of polyclonal antibodies directed versus Ag expressed on the surface of the infection responsible bacteria and/or versus bacteria’s produced substances like endotoxin, peptidoglycans, etc., that are released when the antibiotics cause cellular lysis; the IvIg actually in use belongs from this category, and it is composed by mixtures of IgG, IgM, and IgA in concentrations different than in plasma (Table 3.2). Independently of single composition, the IvIg solutions derive from a plasma pool of 1.000–10.000 donators and so contain a great variety of antibodies directed versus a myriad of different antigens that can vary with the different geographic donator origins and with their exposure on different antigens. The main preparation’s process consists on the extraction and cold fractionation in ethanol, instead, whereas the inactivation of any blood donator virus involves the use of solvents, detergents, the pH reduction to 4, the incubation, the nanofiltration, and the chromatography


Table 3.2
Concentrations of the different classes of IgG in the available preparations


























 
Ig G (%)

IgM (%)

IgD (%)

Normal serum

80

7

13

IgM and IgA IvIg preparations

76

12

12

Other IvIg preparations

≥97

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Sep 22, 2016 | Posted by in ANESTHESIA | Comments Off on Which Among Septic Patients Are the Best Candidate for Immunoglobulins?

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