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 Table of Contents  
REVIEW ARTICLE
Year : 2015  |  Volume : 28  |  Issue : 1  |  Page : 259-265

Immunomodulation in critically ill septic patients


Department of Anaesthesia and Intensive care, Faculty of Medicine, Menoufiya University, Menufia, Egypt

Date of Submission07-Jun-2014
Date of Acceptance18-Aug-2014
Date of Web Publication29-Apr-2015

Correspondence Address:
Mohamed A Azkol
5th floor, House No. 1, Mohamed Elfateh Street, Elestad, Tanta
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.156005

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  Abstract 

Objective
To perform a systematic review on previous trials of immunomodulatory therapies, on current therapies trialed previously and on potential therapies for the near future.
Data analysis
Electronic medical research databases were searched from 1950 or from the starting date of each database. The search was performed on 1 December 2013 and included earlier-published printed articles without language restrictions.
Study selection
The initial search presented 363 articles, of which 30 met the inclusion criteria. The articles were previous trials of immunomodulatory therapies as well as current therapies trialed previously and potential therapies for the near future.
Data extraction
The study quality aimed at achieving ethical approval, prospective design, specified eligibility criteria, the use of appropriate controls, adequate follow-up and defined outcome measures.
Data synthesis
Because of the heterogeneity in follow-up periods and reported outcome measures, it was not possible to pool the data and perform a meta-analysis. Comparisons were made by a structured review.
Recent findings
Numerous trials have been targeted at inhibiting various essential inflammatory mediators and receptors involved in sepsis. This includes the use of activated protein C, corticosteroids, statins and the inhibition of nitric oxide. Hypertonic saline solution, intravenous immunoglobulins, mesenchymal stem cells and colony-stimulating factors have also been tried. Corticosteroids and activated drotrecogin alfa are to date the only drugs that have demonstrated mortality benefits in large randomized controlled trials.
Conclusion
Our knowledge of the pathophysiology of the inflammatory response in sepsis continues to expand. Potential new therapies continue to be developed. Enhanced knowledge of the molecular biology of inflammation may result in improved treatment for septic patients.

Keywords: Critically ill patients, immunomodulation, sepsis, septic shock


How to cite this article:
Helal SM, Hassan GA, Zalat SI, Azkol MA. Immunomodulation in critically ill septic patients. Menoufia Med J 2015;28:259-65

How to cite this URL:
Helal SM, Hassan GA, Zalat SI, Azkol MA. Immunomodulation in critically ill septic patients. Menoufia Med J [serial online] 2015 [cited 2019 Jun 27];28:259-65. Available from: http://www.mmj.eg.net/text.asp?2015/28/1/259/156005


  Introduction Top


Sepsis remains one of the leading causes of mortality in critically ill patients. Sepsis is currently estimated to be the cause of 1.5% of deaths each year [1].Improvement in survival could probably be achieved by earlier adequate antimicrobial therapy, source control and early targeted resuscitation, but a significant proportion of patients do not survive despite appropriate care. Recent research into the pathogenesis of sepsis has led to the development of potential therapeutic strategies that have been shown to decrease mortality rates in large randomized clinical trials [2].

Definition of sepsis

Sepsis is defined as the presence of infection, documented or strongly suspected, with a systemic inflammatory response, as indicated by the presence of the following conditions:

  1. Temperature greater than 38°C or less than 36°C.
  2. Heart rate greater than 90 beats/min.
  3. Respiratory rate greater than 20 breaths/min or PaCO 2 less than 32 mmHg.
  4. White blood cell count greater than 12 000/mm 3 , less than 4000/mm 3 , or greater than 10% immature (band) forms [Table 1] [3].
Table 1 Definitions of diseases relevant to sepsis [3]

Click here to view


Pathophysiological changes of sepsis

Sepsis develops when the initial, appropriate host response to an infection becomes exaggerated [Table 1]. Bacterial components reacting with specific toll receptors are believed to trigger monocytes, neutrophils and endothelial cells to initiate an inflammatory cascade [Figure 1]. Many believe that sepsis develops as a result of the production of proinflammatory molecules such as tumor necrosis factor-a (TNF-a), interleukin-1 (IL-1), IL-6 and IL-8, lysosomal enzymes, superoxide-derived free radicals and vasoactive substances such as platelet-activating factor, tissue factor and plasminogen-activator inhibitor 1 [4].
Figure 1: Inflammatory responses to sepsis [4]. NO, nitric oxide; NOS, nitric oxide synthase; TNF-α, tumor necrosi s factor-α.

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Management of sepsis

The principles in the management of sepsis include the following components [5]:

  1. Early recognition.
  2. Early and adequate antibiotic therapy.
  3. Control of the source of infection including removal or drainage of the infected foci.
  4. Early hemodynamic resuscitation and continued support.
  5. Tight glycemic control.
  6. Use of corticosteroids and drotrecogin alpha.
  7. Proper ventilator management with a low tidal volume in patients with acute respiratory distress syndrome.



  Materials and methods Top


Data analysis

Electronic medical research databases were searched from 1950 or the starting date of each database. The search was performed on 1 December 2013 and included earlier-published printed articles without language restrictions. All the studies were assessed independently for inclusion by two researchers.

Study selection

The initial search presented 363 articles, of which 30 met the inclusion criteria. The articles studied previous trials of immunomodulatory therapies as well as current therapies being trialed and potential therapies in the near future. Article titles and abstracts were initially screened, and then the selected articles were fully read and further assessed for eligibility. All references from the eligible articles were reviewed in order to identify additional studies. As per recommendations, disagreements between researchers were resolved by consensus. All the studies were graded using the criteria for grading studies from the Centre for Evidence-Based Medicine.

Data extraction

The study quality aimed at achieving ethical approval, prospective design, specified eligibility criteria, the use of appropriate controls, adequate follow-up and defined outcome measures.

Data synthesis

Because of the heterogeneity in follow-up periods and reported outcome measures, it was not possible to pool the data and perform a meta-analysis.


  Results Top


Immunomodulation

Immunomodulation is a therapeutic intervention intended to either stimulate or suppress a particular immune response. Immunomodulatory drugs can either be immunosuppressants or immunostimulants and can act on different targets at different levels. They can act through the following means[6]:

  1. Inhibiting or increasing cytokine release.
  2. Affecting cytokine receptor expression.
  3. Affecting the response of cells to cytokines.
  4. Affecting cytotoxic actions of cells.
  5. Affecting phagocytosis.
  6. Regulation of transcription or translation of protein mediators.
  7. Apoptosis modulation.


Immunomodulatory therapies

Antitoxin interventions

Antiendotoxin antibodies
: Early approaches to endotoxin-directed therapy included the administration of nonspecific polyclonal immunoglobulin preparations, anticore endotoxin antibodies and human anti-lipid A antibodies (HA1A). Despite some encouraging results from early studies, none of these strategies have been beneficial in large studies [7].

Bactericidal/permeability-increasing proteins: This agent is released from activated neutrophils and binds to the lipid A component of gram-negative bacterial endotoxin. Initial results in children with meningococcal sepsis have been encouraging [8].

Antimediator interventions

Corticosteroids
: Today, all recommendations for the use of steroids in septic shock are for the administration of 200-300 mg/day of hydrocortisone. Hydrocortisone may be given as boluses or as a continuous infusion. The adjunction of fludrocortisone to hydrocortisone remains controversial. Annane et al. [9] added 50 mg of oral fludrocortisone for its mineralocorticoid effects. In a randomized trial, there was a nonstatistically significant reduction in the mortality with hydrocortisone plus fludrocortisone compared with hydrocortisone alone. Current guidelines recommend slow-tapering steroid doses after 7 days of therapy, with decreasing doses every 2-3 days [10]. The 2008 Surviving Sepsis Campaign Guidelines recommend the use of steroids only in septic shock patients unresponsive to initial treatment with fluids and/or vasopressors [11].

Activated protein C (APC): APC is a component of the natural anticoagulant system. It is a potent antithrombotic serine protease with substantial anti-inflammatory properties. Recombinant human APC [drotrecogin alfa (activated)] was the first biological treatment for serious sepsis approved by the FDA in 2001 [12]. An important feature of the pathophysiology of sepsis is the development of a procoagulant state. Inflammatory cytokines both activate the coagulation cascade and inhibit fibrinolysis. Disseminated intravascular coagulation is a manifestation of the dysregulation of coagulation. APC is a potent anticoagulant and profibrinolytic enzyme capable of inactivating clotting cofactors Va and VIIIa and plasminogen-activator inhibitor 1, thus inhibiting further clot formation and increasing fibrinolysis [13]. The dose of DrotAA, as in the Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) protocol, should be hourly 24 mg/kg of the body weight, administered as a continuous infusion over a period of 96 h [14]. In the PROWESS study, the most benefit of the DrotAA treatment was seen in patients at increased risk of death. On the basis of these data, in 2001, the US FDA and the European Medicines Agency approved the use of DrotAA in patients with severe sepsis at increased risk of death [15].

Nitric oxide (NO) inhibition: Because NO is produced from l-arginine, its production can be inhibited by competitive l-arginine analogues. Nitric oxide synthase inhibition elevates blood pressure and systemic vascular resistance in septic shock patients. NO inhibition has a limited therapeutic potential because it is associated with a progressive decrease in the cardiac output, amplified organ dysfunction and even increased mortality [16].

Hypertonic saline solution: Hypertonic solution was associated with lower levels of TNF-a and with higher levels of the anti-inflammatory cytokine IL-10. Most immunologic and anti-inflammatory effects of hypertonic solutions may be due to an increase in the expression of heat shock proteins [17]. In a study by Nakamura and colleagues, the expression of the 92 kDa gelatinase and l-selectin was suppressed in the hypertonic fluid group compared with the group receiving isotonic fluid. The 92 kDa gelatinase is released from neutrophils and induces capillary leakage by degrading endothelial membranes. High plasma levels of this inflammatory marker is associated with nonsurvival in patients with septic shock [18]. l-Selectin is involved in the adhesion of leucocytes along vessel walls adjacent to the site of injury [19].

Intravenous immunoglobulins: Intravenous immunoglobulins are prepared from pooled plasma from a large number of donors. Traditionally, intravenous immunoglobulins have been used as replacement therapy in patients with primary or secondary immunoglobulin deficiencies. A high dose of intravenous immunoglobulins is used as an immunomodulatory agent in a wide range of autoimmune and inflammatory disorders as well as bacterial and viral infections that do not respond to conventional therapy [20].

Intravenous immunoglobulins have many immunomodulatory actions that may affect the systemic response to sepsis, including [21] the following:

  1. Increased clearance of endotoxins by the reticuloendothelial system.
  2. Enhancement of phagocytosis by neutrophils exposed to different immunoglobulin classes (G, M and A).
  3. Cytokine neutralization by anticytokine antibodies.


Doses of 1-4 g/kg are used, usually fractionating the dose in 4-5 days of infusion, and then repeating the infusion (or a maintenance dose of 0.4 g/kg) every month according to the clinical response [22]. Laupland and colleagues conducted a systematic review and meta-analysis of 14 randomized clinical trials involving 1987 patients, with the aim of determining whether adjuvant therapy with intravenous polyclonal immunoglobulin reduces the mortality among adults with severe sepsis and septic shock. Pentaglobin was the immunoglobulin most often used in the studies. This meta-analysis shows a global reduction in the mortality with the use of intravenous immunoglobulins in the adjuvant treatment of severe sepsis and septic shock in adults [23]. Ballow showed that patients who received the first dose of IgE within 24 h from the onset of severe sepsis or septic shock had a better outcome as compared with those treated later on [24].

Statins: The inhibition of mevalonate synthesis by statins results in the reduction of intracellular inflammatory signalling pathways. The response of the inflammatory intracellular signalling pathway upon stimulation is reduced. The expression of cytokines, acute-phase proteins, chemokines, adhesion molecules and enzymes is partially inhibited in the presence of statins [25].

A double-blind study showed that simvastatin suppressed the expression of toll-like receptors 4 and 2 on the surface of monocytes, which was associated with a decreased circulatory concentration of TNF-a [26]. Statin treatment reduced the relative risk of developing severe sepsis. Admission rates to the ICU were higher among patients not receiving statins than among patients treated with statins (12.2 vs. 3.7%, respectively) [27]. Among 2036 patients admitted with a suspicion of infection, the mortality in the statin group was 1.9 and that in the nonstatin group was 4.4% [28]. Another meta-analysis of patients with sepsis or severe infections also showed a reduction of the morality among patients who were receiving statins [29].

Mesenchymal stem cells: Mesenchymal stem cells (MSCs) are capable of causing a reduction in both local and systemic inflammation by a balanced decrease in proinflammatory cytokine production and an increase in anti-inflammatory cytokine production [30]. MSC-mediated downregulation of proinflammatory cytokines TNF-a, IL-1 and IL-6 also contributes to the diminished inflammatory state [31]. Gonzalez-Rey et al. demonstrated that treatment with MSCs improved bacterial clearance from injured organs significantly, by up-regulating the phagocytic activity of resident macrophages [32].

Hemofiltration

(1) Hemoperfusion (hemoadsorption) : For years, the early utilization of hemoperfusion with polymyxin B in septic shock has been a part of the standard treatment for sepsis caused by gram-negative bacilli in Japan. The mechanism involves the elimination of endotoxins through adsorption, preventing the progression of the inflammatory cascade [33]. A systematic review of 28 studies (nine randomized controlled trials) indicates that hemoperfusion using polymyxin B might indeed beneficially influence hemodynamics and the requirement for vasopressor [34]. Interest in this approach has been renewed as a result of a multicentre study in Italy. This study enrolled 64 patients with severe sepsis or septic shock who underwent emergency surgery for intra-abdominal infection. A total of 34 patients were randomly assigned to receive polymyxin filtration treatment and 30 to receive conventional therapy alone. The investigators reported an increase in the mean arterial pressure, a reduction in vasopressor requirement and a reduced 28-day mortality with polymyxin filtration treatment [35].

(2) Coupled plasmafiltration adsorption : The treatment consists of the separation of plasma from blood with adsorption of the inflammatory mediators and cytokines from plasma, followed by a purification phase using a hemofilter. Animal studies have confirmed the efficacy of this technique, with the elimination of inflammatory mediators, and improved survival [36]. Human studies are limited but promising. It has been demonstrated that coupled plasmafiltration adsorption improved the hemodynamics and the leukocyte responsiveness compared with hemodiafiltration in 10 patients with hyperdynamic septic shock [37].

Anticytokine therapies

(1) Antitumor necrosis factor-a therapy

TNF-a: TNF-a is a multifunctional cytokine with an important role in the immune response, inflammation and the response to injury [38]. TNF-a is thought to play a central role in the pathogenesis of sepsis and septic shock for a number of reasons:

  1. TNF concentrations are increased during clinical and experimental sepsis [39].
  2. Increasing concentrations and especially persistence of high concentrations of TNF during sepsis are associated with nonsurvival [40].
  3. Endotoxin and bacterial challenge in animals and low-grade endotoxin challenge in humans leads to TNF release [41].


TNF-0a inhibitors: There are three TNF-a inhibitors available for clinical use:

  1. Infliximab
  2. Adalimumab
  3. Etanercept


All three agents block the biologic effects of TNF-a, although there are some differences in their structure, pharmacokinetics and mechanisms of action [42]. Both infliximab and adalimumab are anti-TNF-a monoclonal antibodies that bind specifically to human TNF-a with high affinity and neutralize the biological activity of TNF-a by inhibiting its binding to its receptors [43]. Etanercept is not a monoclonal antibody but a fusion protein that acts as a receptor for TNF-a and acts competitively to inhibit the binding of TNF to its cell surface receptor [44].

Anti-TNF-a therapy in sepsis: Attempts to block TNF-a activity have been associated with improved survival in animal models of sepsis and shock [45]. In human studies, 7.5 mg/kg of TNF-a monoclonal antibody provided a significant reduction in mortality 30 days after infusion [42]. A meta-analysis of all randomized controlled clinical studies shows that anti-TNF strategies with monoclonal antibodies are effective in increasing survival, with a mean improvement in survival of 3% [46].

(2) Anti-IL-1 therapy

IL-1 acts synergistically with TNF to produce the hemodynamic effects of septic shock. Interleukin receptor antagonist (IL1-RA) is a natural antagonist of IL-1 and showed some promise in animal studies [47]. A phase-2 clinical trial of recombinant human IL1-RA that involved 99 patients with sepsis suggested that there is a dose-related survival benefit [48]. An initial multicenter study that involved 893 patients supported these findings and suggested that there is a dose-related increase in the duration of survival for patients who had sepsis with organ dysfunction and/or who had a predicted risk of mortality of at least 24% [49]. However, a second phase-3 trial was terminated after an analysis showed no significant differences in mortality rates [50].

Immunostimulation

Colony-stimulating factors

The neutrophil, or the polymorphonuclear leukocyte, is a key cell in the host defense against microbial pathogens. Several studies have shown that the neutrophil function in septic patients may be abnormal, including reduced migration and defective bacterial killing with an increase in susceptibility to infection. This condition is called immunoparalysis. Colony-stimulating factors are glycoproteins that bind to the surface of hemopoietic stem cells. They activate stem cells to proliferate and differentiate into a specific kind of blood cell, usually white blood cells. Colony-stimulating factors have also been demonstrated to improve the polymorphonuclear leukocyte function, and this may improve the outcome of sepsis [51]. Researchers have observed that granulocyte colony-stimulating factor (G-CSF) administration improved the survival in animals with gram-negative sepsis [52]. In a study that involved 78 patients with burn-related sepsis, G-CSF treatment improved the outcome [53]. In a follow-up study that involved 480 patients, there were reduced mortality rates among patients with pneumococcal pneumonia who received G-CSF [54].


  Discussion Top


The prominent role of inflammatory molecules and pathways suggests a possible therapeutic role in the management of severe sepsis and septic shock. Numerous trials have been targeted at inhibiting various essential inflammatory mediators and receptors involved in sepsis. This includes the use of antitoxin interventions, APC, corticosteroids, statins and the inhibition of NO. Hypertonic saline solution, intravenous immunoglobulins, MSCs, hemofilteration, anticytokine therapies and colony-stimulating factors have also been tried. Corticosteroids and activated drotrecogin alfa are to date the only drugs that have demonstrated mortality benefits in large randomized controlled trials.


  Conclusion Top


Our knowledge of the pathophysiology of the inflammatory response in sepsis continues to expand. Potential new therapies continue to be developed. Enhanced knowledge of the molecular biology of inflammation may result in improved treatment for septic patients [55].


  Acknowledgements Top


Author contributions: Mohamed A. Azkol: collection and analysis of data for the work; Prof Dr Ghada A. Hassan and Prof Dr Safaa M. Helal: assessment of all the studies for inclusion achieving ethical approval, prospective design, specified eligibility criteria, the use of appropriate controls and adequate follow-up, analysis and interpretation of the review data, revision of the final review form; Dr Sherif I. Zalat: contribution to collection and analysis of the review data.

Conflicts of interest

There are no conflicts of interest.

 
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