Our current understanding of sepsis and multiple organ dysfunction needs to be revised, as the uniformly negative results of new therapies for these disorders suggest. Previous theories for the pathogenesis of these conditions are incomplete; reasons for this include the following. First, the surrogate models that have been used to study these disorders are not analogous to the clinical situation. Second, patients who have less severe manifestations of these diseases are often overlooked. And third, patients' preexisting conditions have not been taken into account. Considerable new evidence indicates that, in addition to a massive proinflammatory reaction, a compensatory anti-inflammatory response contributes to the onset of these disorders. At a local site of injury or infection and during the initial appearance of pro- and anti-inflammatory mediators in the circulation, the beneficial effects of these mediators outweigh their harmful effects. Only when the balance between these two forces is lost do these mediators become harmful. Sequelae of an unbalanced systemic proinflammatory reaction include shock, transudation into organs, and defects in coagulation. An unbalanced systemic compensatory anti-inflammatory response can result in anergy and immunosuppression. The proinflammatory and anti-inflammatory forces may ultimately reinforce each other, creating a state of increasingly destructive immunologic dissonance.

Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS)

INTRODUCTION 380 SEPSIS AND SEPTIC SHOCK 380 BACTERIAL CELL WALL ARCHITECTURE 381 Lipopolysaccharide 381 Lipoteichoic and Teichoic Acids 383 Peptidoglycan 383 Purification and Aggregate Structure 383 HOST RESPONSE TO CELL WALL CONSTITUENTS 384 Cellular Defense 384 Humoral Defense 385 The Liver 385 Liver cell types 386 Experiments with Radiolabeled Lipopolysaccharide In Vivo 386 Macrophages and the Response to Lipopolysaccharide and Lipoteichoic Acid 386 Detoxification of Lipopolysaccharide 387 LIPOPOLYSACCHARIDE AND LIPOTEICHOIC ACID RECEPTORS 387 Lipopolysaccharide-Binding Protein 388 CD14 388 sCD14 389 Toll-Like Receptors 390 2-Integrins 392 Selectins 393 Scavenger Receptors 393 Moesin 394 Heptose-Specific Lipopolysaccharide Receptor 394 LIPOPOLYSACCHARIDEAND LIPOTEICHOIC ACID-BINDING PROTEINS 394 Neutrophilic Lipopolysaccharide-Binding Molecules 394 Bactericidal/permeability-increasing protein 394 CAP18 394 CAP37 395 Lactoferrin 395 Lysozyme 395 Other Lipopolysaccharide-Binding Proteins 395 Development of Bactericidal and Lipopolysaccharide-Neutralizing Peptides 395 LIPOPROTEINS 395 Metabolism 395 Apolipoprotein E 396 Anti-Inflammatory Role 396 Lipid Metabolism and Infection 398 CLINICAL AND EXPERIMENTAL SEPSIS THERAPIES 399 Immunosuppression and Neutralization of Proinflammatory Cytokines 400 CONCLUDING REMARKS 400 REFERENCES 401

https://biorxiv.org/content/biorxiv/early/2016/04/07/047647.full.pdf

Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock

Endotoxemia in human septic shock.

https://www.cell.com/trends/molecular-medicine/pdf/S1471-4914(14)00009-4.pdf

Why have clinical trials in sepsis failed

Steven M. Opal, MDPierre-Francois Laterre, MDBruno Francois, MDSteven P. LaRosa, MDDerek C. Angus, MD, MPHJean-Paul Mira, MD, PhDXavier Wittebole, MDThierry Dugernier, MDDominique Perrotin, MDMark Tidswell, MDLuis Jauregui, MDKenneth Krell, MDJan Pachl, MDTakeshi Takahashi, MDClaus Peckelsen, MDEdward Cordasco, DOChia-Sheng Chang, MDSandra Oeyen, MDNaoki Aikawa, MD, PhDTatsuya Maruyama, MD, PhDRoland Schein, MDAndre C. Kalil, MD, MPHMarc Van Nuffelen, MDMelvyn Lynn, PhDDaniel P. Rossignol, PhDJogadish Gogate, PhDMary B. Roberts, MSJanice L. Wheeler, BS, RNJean-Louis Vincent, MD, PhDfor the ACCESS Study Group

https://biblio.ugent.be/publication/4222072/file/4222102.pdf

Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients With Severe Sepsis

In an effort to decrease deaths from gram-negative bacteremia and endotoxin shock, we treated bacteremic patients with human antiserum to endotoxin (lipopolysaccharide) core. Antiserum was prepared by vaccinating healthy men with heat-killed Escherichia coli J5; this mutant lacks lipopolysaccharide oligosaccharide side chains, so that the core, which is nearly identical to that of most other gram-negative bacteria, is exposed for antibody formation. In a randomized controlled trial, patients were given either J5 antiserum or preimmune control serum intravenously, near the onset of illness. The number of deaths in the bacteremic patients was 42 of 109 (39 per cent) in controls and 23 of 103 (22 per cent) in recipients of J5 antiserum (P = 0.011). In those with profound shock, mortality was 30 of 39 (77 per cent) in controls and 18 of 41 (44 per cent) in recipients of J5 antiserum (P = 0.003). We conclude that human antiserum to the lipopolysaccharide core can substantially reduce deaths from gram-negative bacteremia.

E. J. Ziegler

Papers

Treatment of gram-negative bacteremia and shock with human antiserum to a mutant escherichia coli