Pathogenesis of sepsis Flashcards
What is sepsis (general)
Sepsis is defined as SIRS in response to an infectious process
Systemic Inflammatory Response Syndrome (SIRS)
Fever - >38 degrees or <36 degrees
Tachypnoea - > 20 rpm or PaCO2 <32mmHG
Tachycardia - >90bpm
Leucocytosis/leucopenia - >12000 ul^-1 or <4000 ul^-1
> or equal to 2 out of 4 required
- Infection (proven or probable)
Problems with SIRS criteria
Too sensitive - may represent a healthy response to infective process
Too non-specific - many SIRS patients have non-infective process
- ‘Infection’ (proven or probable) - too nebulous. Patients with sepsis easily missed
Sepsis 3 criteria
- Organ dysfunction
- Dysregulated host response
- Infection
Immunopathology of sepsis - the endotoxin paradigm
Sepsis begins with wide-spread recognition of generic microbial elements (eg lipopolysaccharide)
- gram negative LPS binding protein (endotoxin)
- CD14
- Toll like receptors (monocyte/macrophage, endothelium) - tLR4
- Receptor associated kinases
- Regulation of cytokine gene transcription
Pathophysiology of sepsis
Pro-inflammatory cytokines
- Increase in vascular permeability
- Decrease in vascular resistance
- Decrease in cardiac contractility
- Fever, diarrhoea
- Metabolic changes (insulin resistance, protein catabolism)
- increase in neutrophil migration, adhesion
- Increase in coagulation
Cardiovascular changes in sepsis
Early distributive shock(warm peipheries) - peripheral vasodilatation
Then hypovolaemic shock(cold peropheries) - capillary leak, peripheral and pulmonary oedema, low filling pressure(fluid responsive)
Late cardiogenic shock(cold peripheries) - cardiac myocyte suppression, high filling pressure (not fluid responsive)
Coagulation response in sepsis
Coagulation homeostasis disrupted early and profoundly in sepsis
- Platelet activation
- Activation of coagulation cascades
- Down-regulation of anticoagulant mediators
- Consumption of coagulation factors
- Coagulation and inflammation closely linked
Coagulation factors –> pro-inflammatory activity
Anticoagulation factors –> anti-inflammatory activity
Coagulopathy in sepsis
Intrinsic ‘contact activation’ pathway
Loss of endothelial integrity –> VIII –> thrombin –> fibrin clot
Extrinsic ‘tissue factor’ pathway
Monocyte –> IL1, TNF-alpha –> TF-VII–. Thrombin –> fibrin clot
What is consumption coagulopathy (disseminated intravascular coagulation)
- Acquired disturbance of blood clotting leading to an increased turnover of coagulation factors and platelets by which the production sites are being exhausted
Metabolic changes in sepsis
- Protein catabolism
- Insulin resistance
- Decrease in tissue oxygen uptake (altered mitochondrial function)
What do circulatory changes, coagulation and metabolic changes in sepsis lead to
Tissue hypoxia –> lactic acidosis
Other examples of PAMPS in sepsis
- Lipopeptides
- Peptidoglycans
- Flagellin
- Microbial DNA/RNA
Other examples of PRRs in sepsis
- TLRs1-11
- CD14
- NOD1 and 2
- Beta integrins
- Mannose binding lectin
Sepsis aetiology
- Constantly changes
- 1980s predominantly gram negative
- 1990s-2000s emergence of gram positives
- 2010s emergence of yeasts, re-emergence of gram negatives - Varies geographically
e. g. case mix - Major changes in paediatrics with vaccination - disappearance of meningococcus, hemophilus, pneumococcus
Gram positive sepsis
Gram positive bacteria - no LPS Activation of innate immune processes - peptidoglycans - lipotechoic acid In vitro less potent than LPS But same fundamental mchanisms apply
Superantigen exotoxins
- Staph aureus
- Strep pyogenes
Specific form of sepsis ‘toxic shock syndrome’
Presentation of toxic shock syndrome
- Fever
- Confusion, diarrhiea
- Generalised erythema
- Fulminant hypotension
- Renal failure
- 5% mortality
- Desquamation of palms and soles
- S.aureus producing toxic shock syndrome toxin - 1 (TSST-1)
S.aureus toxic shock
New strains of S. aureus (TSST-1)
- Tampon shock still seen occasionally
- Burns patients - high rates of S. aureus
- ICU - especially neonatal ICU
- Nasal and surgical packs
Streptococcal toxic shock syndrome
S. pyogenes (group A streptococcus)
- Following deep seated S. pyogenes infections (necrotising fascitis, myositis, septic arthritis etc)
Strep toxic shock syndrome mortality rate
20-50%
Immunopathogenesis of toxic shock
Protein exotoxins of certain bacteria
Function immunologically as superantigens
Antigens - trigger T cell responses in tiny proportions of resting T cells
Superantigens - trigger T cell responses in up to 20% of all resting T cells
Features of superantigen responses
- Not restricted by antigen specificity of cells
- Big
Conventional antigen presentation vs superantigen presentation
Conventional - 1/10^5 T cells activated. CD4 T cells
Superantigen - Up to 1/5 T cells activated CD4 and CD8 T cells
- IL2, IFNgamma - T cell
- TNFalpha, IL1beta - APC
