Sepsis results from the interaction of the infectious agent, usually bacteria, with the host’s immune, cardiovascular, neuronal, metabolic, and coagulation systems. Some degree of inflammatory response to infection is normal, but when this response is dysregulated, an excess of pro- and anti-inflammatory mediators leads to organ dysfunction.
Sepsis caused by gram-negative bacteria is mediated primarily by endotoxin, also known as lipopolysaccharide (LPS). The main effects of LPS are caused by its lipid A component. Lipid A combines with LPS-binding protein, and together are bound by Toll receptor 4 (TLR4), a pattern recognition receptor (PRRs) on the surface of macrophages and other innate immune cells, as well as B cells. When macrophage TLR4 is activated, this stimulates the production of interleukin-1 (IL-1), tumor necrosis factor (TNF), and IL-6. These cytokines cause fever, alter the endothelial cells to cause vascular leak, and recruit and activate inflammatory white blood cells. Nitric oxide is also released, causing vasodilation and hypotension, contributing to hypotension (see Chapter 58). Figure 79–1 describes the processes that occur in endotoxin-mediated septic shock. The effects of endotoxin are discussed in more detail in Chapter 7 on Bacterial Pathogenesis.
Processes involved in endotoxin-mediated septic shock. Endotoxin (LPS) from gram-negative bacteria binds to LPS-binding protein, a normal component of blood plasma. This complex binds to Toll-like receptor (TLR)-4 on the surface of macrophages. Activation of TLR-4 induces the synthesis of inflammatory cytokines resulting in the manifestations of sepsis. DIC = disseminated intravascular coagulation; IL = interleukin; LPS = lipopolysaccharide; TNF = tumor necrosis factor.
Endotoxin also activates the coagulation cascade, causing disseminated intravascular coagulation (DIC). Endotoxin initiates DIC by stimulating endothelial cells to produce tissue factor. The end result of this cascade is the formation of thrombi (composed of fibrin) in capillaries throughout the body, blocking the flow of blood, and resulting in anoxia of vital organs. Petechial hemorrhages and purpuric lesions occur when blood leaks into the tissue spaces at the site of endothelial cells damaged by anoxia (Figure 79–2).
Disseminated intravascular coagulation (DIC). Note purpuric lesions on leg caused by endotoxin-mediated DIC in a patient with meningococcemia. (Reproduced with permission from Wolff K, Johnson R. Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology. 6th ed. New York, NY: McGraw-Hill Education; 2009.)
Sepsis caused by gram-positive bacteria is not mediated by endotoxin because these bacteria do not contain LPS. Rather, there are surface components such as peptidoglycan and teichoic acid that stimulate the macrophage, through PRRs other than TLR4, to produce the inflammatory mediators mentioned above. Similarly, some fungi, viruses, and protozoa have elements that can trigger macrophages to generate the same effect.
Often sepsis is marked by an elevation in total blood leukocytes, especially neutrophils, but it can be accompanied by a reduction in the number and function of leukocytes, particularly B and T lymphocytes. This limits the adaptive host response, enhances the severity of the infection, and further augments the impact of sepsis.
A predisposition to sepsis occurs in the very young (neonatal sepsis), the very old, those with reduced host defenses, and people with chronic diseases such as diabetes, chronic hepatitis, and kidney failure.
Neonatal sepsis is the result of the infant’s immature immune system coupled with carriage of the bacteria in the female genital tract that are transmitted during the passage through the birth canal. The most common causes are Group B streptococci (Streptococcus agalactiae), Escherichia coli, and Listeria monocytogenes.