Abstract
Endotoxin detection in human patients has been a difficult challenge, in part due to the fact that the conserved active portion of the molecule (lipid A) is a relatively small epitope only amenable to binding by a single ligand at any one instance and low levels (pg/ml) are capable of stimulating the immune system. The endotoxin activity assay, a bioassay based on neutrophil activation by complement opsonized immune complexes of lipopolysaccharide (LPS), has allowed the specific detection of the lipid A epitope of LPS in a rapid whole blood assay format. This review summarizes diagnostic studies utilizing the endotoxin activity assay in a variety of hospital patient populations in whom endotoxin is postulated to play a significant role in disease etiology. These include ICU patients at risk of developing 'sepsis syndrome', abdominal and cardiovascular surgery patients and patients with serious traumatic injury. Significant features of these studies include the high negative predictive value of the assay (98.6%) for rule out of Gram-negative infection, ability to risk stratify patients progressing to severe sepsis (odds ratio 3.0) and evidence of LPS release in patients with gut hypoperfusion. Preliminary studies have successfully combined the assay with anti-LPS removal strategies to prospectively identify patients who might benefit from this therapy with early evidence of clinical benefit.
Highlights
The investigation of the role of endotoxin, known as lipopolysaccharide (LPS), in the pathophysiology of sepsis in patients who are treated in hospitals has been pursued since LPS was first discovered in the 1800s as aGram-negative cell wall toxin capable of triggering lethal shock
A subsequent litany of anti-endotoxin therapies attempting to block the toxic effects of lipid A have failed US Food and Drug Administration (FDA) clinical trials and have included monoclonal antibodies (E5, HA1A), binding peptides (bactericidal/permeability increasing peptide (BPI)), phospholipid emulsions, lipid A antagonists (Eritoran) and toll like receptor (TLR)4 antagonists (TAK-242)
Other studies cited in this review, including those in pediatric patients undergoing surgical repair of congenital heart defects, cardiopulmonary bypass patients and patients with severe polytrauma, suggest that gut injury due to hypoperfusion may release LPS into the systemic circulation and that this toxin may play a synergistic role in the genesis of multi-organ failure
Summary
The investigation of the role of endotoxin, known as lipopolysaccharide (LPS), in the pathophysiology of sepsis in patients who are treated in hospitals has been pursued since LPS was first discovered in the 1800s as a. The investigators concluded that children undergoing surgery for repair of congenital heart defects are at increased risk for intestinal mucosal injury and endotoxemia, which may exacerbate postsurgical recovery They suggested that endotoxin assays may be useful to guide the use of anti-LPS or immunomodifying therapies in these patients. In a separate study population composed of 19 pediatric living donor liver transplants, Sandana and colleagues [26] compared EA with the LAL assay by measuring peripheral and portal vein endotoxin levels preoperatively They found significantly increased endotoxin levels in the portal blood samples compared to peripheral blood (P < 0.05). The authors concluded that the EAA was superior to the LAL, even at low endotoxin levels and reflected hepatic clearance
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