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CHAPtER 27 Host Defenses to Extracellular Bacteria 399

FcγIIa (CD32) receptor polymorphisms, Fcγ-receptor III (CD16), TABLE 27.5 Examples of Extracellular
MBL, TLR4, tumor necrosis factor (TNF) promoter region Bacteria Causing Sepsis by Presumed Site
polymorphisms, plasminogen activator and inhibitor expression, of Infection
and hereditary differences in cytokine induction influence
susceptibility to meningococcemia. Each of these polymorphisms Lung Streptococcus pneumoniae, Haemophilus
can influence the course of invasive bacterial infection by influenc- influenzae, Pseudomonas aeruginosa
ing the response of the inflammatory cascade. Abdomen Escherichia coli, mixed anaerobic infections
Urinary tract E. coli, Klebsiella spp., Enterobacter spp.,
Enterococcus spp.
tHERAPEUtIC PRINCIPLES Soft tissue Streptococcus pyogenes, Staphylococcus
Sepsis aureus, polymicrobial
Intravenous line S. aureus, Candida spp.
• Early effective antibiotic therapy associated with improved Other Neisseria meningitides
outcomes
• Lack of “source control” (e.g., removal of infected lines, drainage of
abscesses) linked to poor outcomes even in the presence of effective
antibiotics (e.g., LPS) and intracellular environments (e.g., DNA fragments)
• Intensive and supportive care, management of fluid, electrolytes, and (see Table 27.3) The severity of sepsis is also influenced by
respiratory function polymorphic alleles of genes involved in the inflammatory
• Insulin for glucose control—unknown mechanism of protection; cascade. 35
neutrophils have impaired function in the presence of hyperglycemia,
insulin can have antiapoptotic effects
KEY CONCEPtS
DELETERIOUS HOST RESPONSES Definitions of Sepsis and Septic Shock (Third
International Consensus Definitions for Sepsis
Inflammation and Autoimmunity and Septic Shock) 42
The host immune response can be the leading cause of tissue
injury in the acute phase of an infection. Brain edema and infarcts, • Sepsis—life-threatening organ dysfunction causes by dysregulated
host response to infections (including nonbacterial pathogens)
which are devastating consequences of pyogenic meningitis, occur • Septic shock—subset of patients with sepsis with increased risk
as a result of the host inflammatory response. Corticosteroids of death due to profound circulatory, cellular, and metabolic
are currently recommended as an adjunctive therapy to pneu- abnormalities
mococcal meningitis, an acute pyogenic infection. The use of • SIRS (systemic inflammatory response syndrome)—nonspecific
small molecules targeting specific immunological pathways is response to infectious and noninfectious insults; current guidelines
an area of ongoing research. As acute infections are initially recommend use of qSOFA (Quick Sequential Organ Failure Assessment
Score) score in lieu of SIRS criteria, given its higher predictive value
characterized by an inflammatory response followed by an for sepsis
antiinflammatory response, the timing of use of these compounds
is of the utmost importance. 35,36 Infections can lead to autoimmune
diseases. Molecular mimicry between a bacterial antigen and a The morbidity and mortality of bacteremia and sepsis have
host protein is a mechanism of generation of autoantibodies. been directly correlated with the initial levels of proinflammatory
Examples include rheumatic fever and glomerulonephritis after cytokines and the amount of circulating bacterial components.
S. pyogenes infections, reactive arthritis following Chlamydia Indeed, the severity of gram-negative sepsis has been equated
trachomatis urethritis, and the Guillain-Barré syndrome following with high levels of endotoxin, increased levels of cytokines, and
Campylobacter jejuni enteritis. Molecular mimicry can also limit excessive activation of the AP. Disseminated intravascular coagula-
selection of epitopes for vaccine development. tion, which often accompanies gram-negative sepsis, is caused
by excessive activation of the coagulation cascade and downregula-
Sepsis tion of the fibrinolytic system associated with high levels of LPS.
Septicemia remains a leading cause of death in the United States Levels of natural anticoagulants in the vasculature, such as
and accounts for several billion dollars in health care expendi- antithrombin and protein C, are often low in gram-negative
ture. 35,36 Both gram-negative and gram-positive bacteria can sepsis. The onset and severity of disseminated intravascular
rapidly multiply in the bloodstream and trigger sepsis and septic coagulation may be influenced by genetic polymorphisms in
shock (Table 27.5). Septic shock is a result of an initial and plasminogen activation or inhibition. The generalized, altered
widespread systemic proinflammatory response, resulting in vascular endothelial lining facilitates thrombosis and thrombo-
hypotension, organ failure, and death. The later phase of sepsis cytosis. Although much remains to be learned about the mecha-
is also characterized by an antiinflammatory response. Although nisms by which gram-negative and gram-positive bacteria and
survival of patients with the acute phase of sepsis has improved, microbial products trigger sepsis, significant advances have been
advances on treatment and prevention of death, which can be made recently, particularly with endotoxin-mediated sepsis.
secondary to nosocomial infections, have been slower. These Advances during the past decade include the identification of
secondary infections are often caused by less virulent organisms, certain LPS–host protein interactions that result in delivery of
likely as a result of “immunoparalysis” (as a result of an exag- LPS to host cell receptors and gene activation events that result
gerated antiinflammatory reaction) and also breaching of the in elevated expression of a diverse array of proinflammatory
physical barriers to infection as a result of invasive medical and antiinflammatory mediators (Fig. 27.6).
procedures (e.g., intravenous lines, intubation, and bladder For example, TLR4 signaling requires an accessory protein,
catheterization). The systemic inflammatory cascade of sepsis myeloid differentiation protein-2 (MD-2), which binds directly to
37
is initiated by recognition of PAMPs by PRR, both in extracellular endotoxin. The key point, however, is that the LPS engagement