SIR ROBERT MUIR, SEPSIS AND SCOTTISH HEALTHCARE

Muir discusses septicaemia in the infection chapter of his textbook, and looks at the pathogenesis of disease from the viewpoint of the invading bacteria only, and does not really consider the host's immune response as contributing to the severity of disease. Today, the manifestations of sepsis are largely considered a result of an extreme host response, and can be defined as a systemic inflammatory response system (SIRS) after severe microbial or fungal infection. In 2009 a review of an international severe sepsis demonstrated that of 11000 patients on the register, 44% had gram positive infections, 57% had gram negative and 11% had fungal infections. Some of these patients had combined infection, hence the total is >100%. Causative agents of septicaemia include Listeria monocytogenes, Neisseria meningitides, and Group B streptococcus. Of the 11000 registered patients, the mortality rate was almost 50%, underlining the severity of the pathology. The main site of infection was the lung, accounting for 47% of cases, followed by the abdomen (23%) and urinary tract (8%). 

In a normal bacterial or fungal infection the immune system can overcome the invading organisms. In septicaemia, the body has to fight so hard to remove the infection that there is a huge amount of collateral damage, which can result in multiple organ failure and ultimately death. A large proportion of tissue damage in the infected host is due to microbial toxins and the patient’s response to these. There are three classes of toxins used by bacterial pathogens to damage hosts. Type 1 toxins injure the host by binding to receptors on host cell membranes and initiating intracellular signalling pathways. Staphylococcus aureus is a bacterial infection that causes septicaemia and works using type 1 toxins. S. aureus ligate MHC class II protein on antigen presenting cells with T cell receptors on the surface of CD4 T cells, resulting in massive activation of T cells and extreme secretion of pro-inflammatory cytokines. Type II toxins damage host cell membranes in order to interrupt the host response to bacteria and also to allow the bacteria to force entry into the host cell. Type II toxins include pore-forming toxins such as cholesterol-dependent cytolysins, which form a pose of 25-30nm in diameter in the host cell wall. Type III toxins are classified according to their entry mode into cells. Type III toxins are made up of two components, an active enzymatic moiety linked to a specific binding component. Bacterial toxins such as anthrax toxin and cholera toxin are type III toxins.  Using a variety of these three toxin systems, bacterial pathogens gain entry into human host tissues.

Bacterial co-operation is now seen as a key factor in the virulence of infection. Quorum sensing is the ability of bacteria to determine bacterial population density around them.  Quorum sensing systems (QSSs) are widespread among common bacterial causes of septicaemia. Once the bacterial population gets to a certain size, QSSs cause the bacteria to transcribe certain virulence genes, including anti-complement and anti-phagocytic measures, as well as the production of the aforementioned toxins.