Author’s note: The following discussion is based on a presentation delivered at the 2001 annual meeting of the AACC in Chicago by Patrick Scannon, M.D., Ph.D., Senior Vice President and Chief Scientific and Medical Officer of XOMA Ltd., a developer and manufacturer of innovative biopharmaceuticals specializing in products for the treatment of cancer, infectious diseases, and immunological and inflammatory disorders.

Sepsis kills over 250,000 Americans of all ages every year. It is the number one cause of death in noncoronary critical care units, often evading diagnosis until the advanced stages. Statistics from the Centers for Disease Control and Prevention indicate that the incidence is on the rise.¹ Recent developments, however, may soon lead to genuine progress in providing timely, accurate diagnosis and treatment of sepsis.

Currently, sepsis is recognized as a heterogeneous clinical syndrome, typically associated with underlying conditions and triggered by many kinds of microbes. It occurs when the body experiences a systemic inflammatory response to a bacterial, viral or fungal infection, and is manifested by increased respiratory and heart rates, hypo- or hyperthermia, and an increased or decreased white blood cell count. The resulting sepsis-inducing inflammatory cascade can produce complications such as hypotension, acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC) and multiple organ failure, which can lead to septic shock and death.

The only primary treatments available to US clinicians are antibiotics and intensive care support such as ventilators and hemodialysis, in cases of organ failure. Although the many attempts at sepsis cures have been generally disappointing, current research shows promise. One of the more encouraging treatments, a recombinant activated protein C product called Xigris™, has demonstrated a significant reduction in 28-day mortality in patients with severe sepsis.² Eli Lilly has received an approvable letter for this product from the FDA. Other investigational approaches involve attempts to block the inflammatory cascade itself, target the microbes causing the infection, or counter the effects of microbial products such as endotoxin or lipotechoic acid.

Rapid diagnosis and treatment of sepsis is imperative. Clinicians cannot wait for a culture to become positive, but must presume the presence of infection and administer antibiotics immediately. Unfortunately, diagnosis is complicated, and sepsis can occur under many conditions. As case studies have shown, anyone can become a victim of sepsis, from bone marrow recipients to marathon runners.

A great demand exists for in vitro diagnostic markers of sepsis, and numerous markers are under consideration. As a nonspecific inflammation marker, C-reactive protein (CRP) may be useful as an early indicator of systemic inflammatory response. Endogenous activated protein C is another marker with potential, although it is currently used only in conjunction with Xigris therapy. Research involving cytokines has generated tremendous enthusiasm in the infectious disease and critical care community, and proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-6 (IL-6) and anti-inflammatory cytokines such as interleukin-10 (IL-10) show promise as sepsis markers. Relating blood cytokine levels to the septic process, however, has proved challenging.

Researchers are also considering the use of endotoxin (lipopolysaccharide, LPS) as a sepsis marker. Endotoxin is released from the cell walls of gram-negative bacteria and is one of the most potent inducers of inflammation known. During the septic process, the barrier between the gastrointestinal (GI) tract and the bloodstream can become compromised by sepsis-induced circulation impairment, causing endotoxin from bacteria in the GI tract to enter the blood stream. Endotoxin is released into the blood only sporadically, however, and its short half-life in circulation makes the timing of sample collection critical, creating a serious concern over false-negative test results. The neutrophil chemiluminescence assay, which measures endotoxin activity (EA), is a new approach to measuring endotoxin and is currently undergoing FDA review. This assay also has its limitations, however, since the timing of sample collection is still crucial for avoiding false negatives, and the assay must be conducted immediately on fresh blood samples.

Another marker, lipopolysaccharide binding protein (LBP), is under investigation by researchers at DPC and other facilities. LBP is a plasma protein produced continuously by the liver, its rate of production being rapidly increased in response to the presence of LPS in the blood. It is elevated in all types of sepsis and forms a complex with LPS. The complex binds to the CD14 receptors of monocytes, inducing the inflammatory cascade. As a sepsis marker, LBP has some advantages over LPS. It has a much longer half-life in vivo than LPS, making timing of sample collection less critical. Moreover, LBP present in a patient sample represents the patient response: this may not always be the case with LPS assays, where external contamination may account for measurable levels.

As sepsis remains a large and growing problem, there is still a great need for new diagnostics and therapies. Immunoassays for the measurement of cytokines, LPS and LBP may prove to be the diagnostic tools of the future in the effort to gain the upper hand on sepsis.

DPC supports sepsis diagnostics research with IMMULITE^® inflammation marker assays, the only such assays currently available in an automated format.

References
1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky
MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome and associated costs of care. Crit Care Med 2001;29:1303-10.

2. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A,et al. Efficacy and safety of recombinant human activated protein
C for severe sepsis. Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. N Engl J Med 2001 Mar 8;344(10):699-709. [Comment in: N Engl J Med. 2001 Mar 8;344(10):759-62.]

Additional Reading
American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit. Care Med 1992 Jun;20(6):
864-75.

Grinnell BW, Joyce D. Recombinant human activated protein C: a system modulator of vascular function for treatment of severe sepsis. Crit Care Med 2001 Jul;29(7 Suppl):S53-60.

Kanji S, Devlin JW, Piekos KA, Racine E. Recombinant human activated
protein C, drotrecogin alfa (activated): a novel therapy for severe sepsis. Pharmacotherapy 2001 Nov;21(11):1389-402.

Martin GS. Current management strategies for severe sepsis and septic shock. Abstract presented at the Chest 2001 Annual Meeting (67th Annual Scientific Assembly of the American College of Chest Physicians); 2001 Nov 4-8; Philadelphia. http://www.medscape.com/medscape/cno/2001/chest/Story.cfm?story_id=
2547 (accessed December 2001).