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What is the pathophysiology of the septic host upon admission?
Evangelos J Giamarellos-Bourboulis1
14th Department of Internal Medicine, Attikon University Hospital, Athens, Greece. giamarel@ath.forthnet.gr
Abstract:
The enormous case-fatality rate of severe sepsis and septic shock has resulted in considerable efforts being made towards understanding their complex mechanisms of pathogenesis. This has been done with the hope that agents that interfere with the pathways of pathogenesis and modulate the immune response of the host may be candidates for therapy. Disappointing results from most trials of immunomodulators in sepsis have led to understanding that the progression of patients to multiple organ dysfunction syndrome involves blunting of the pro-inflammatory cytokine storm. Instead, the compensatory anti-inflammatory response syndrome (CARS) develops, which is characterised by immunoparalysis. Components of this syndrome are impaired phagocytosis by neutrophils, decreased expression of HLA-DR on monocytes, impairment of ex vivo cytokine stimulation of monocytes, CD4 lymphopenia due to apoptosis of lymphocytes and predominance of anti-inflammatory T(h)2 and regulatory T-cell responses over pro-inflammatory T(h)1 and T(17) responses. CARS is not the sole explanation for the failure of trials of immunomodulators in sepsis. Recent data from the Hellenic Sepsis Study Group demonstrate that components of CARS upon transition from sepsis to severe sepsis/shock differ in relation to the underlying type of infection. These data underscore that the pathogenesis of sepsis presents considerable heterogeneity from one patient to another. That heterogeneity should be taken into consideration when deciding to administer an immunomodulator.
Insights
Severe sepsis and septic shock pathogenesis involves immune system shifts, including compensatory anti-inflammatory response syndrome (CARS). Understanding infection-specific CARS heterogeneity is crucial for effective immunomodulator therapy in sepsis patients.
Area of Science:
- Immunology
- Pathogenesis of Sepsis
- Critical Care Medicine
Background:
- Severe sepsis and septic shock have high mortality rates, driving research into pathogenesis.
- Therapeutic strategies targeting immune response modulation have yielded disappointing results.
- Understanding the immune dysregulation in sepsis is key to developing effective treatments.
Purpose of the Study:
- To elucidate the complex pathogenesis of severe sepsis and septic shock.
- To investigate the role of the compensatory anti-inflammatory response syndrome (CARS) in sepsis progression.
- To explore the heterogeneity of CARS based on infection type and its implications for immunomodulator therapy.
Main Methods:
- Review of current understanding of sepsis pathogenesis and immune response.
- Analysis of components of CARS, including neutrophil function, monocyte HLA-DR expression, and lymphocyte apoptosis.
- Examination of T-cell responses (Th1, Th2, Th17, regulatory T cells) in sepsis.
- Consideration of recent data on CARS heterogeneity in sepsis transitioning to severe sepsis/shock.
Main Results:
- Sepsis progression to multiple organ dysfunction syndrome involves blunting of pro-inflammatory responses and development of CARS, characterized by immunoparalysis.
- CARS involves impaired neutrophil phagocytosis, decreased monocyte HLA-DR expression, and altered T-cell responses.
- Recent findings indicate that CARS components vary depending on the underlying infection type.
- This heterogeneity in sepsis pathogenesis must be considered for immunomodulator administration.
Conclusions:
- The compensatory anti-inflammatory response syndrome (CARS) plays a significant role in sepsis pathogenesis and treatment failure.
- Patient-specific heterogeneity in CARS, influenced by infection type, is a critical factor in sepsis progression.
- Tailoring immunomodulator therapy based on the specific characteristics of sepsis and the host immune response is essential for improved patient outcomes.
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