The Reply

Abstract

Pramod and Singh1Pramod J. Singh A. Sepsis biomarkers.Am J Med. 2008; 121 (xx-xx)Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar question the omission of biomarkers, particularly procalcitonin, from our review of sepsis.2O'Brien Jr, J.M. Ali N.A. Aberegg S.K. Abraham E. Sepsis.Am J Med. 2007; 120: 1012-1022Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar They suggest that such biomarkers have a role in early detection and follow-up of septic patients. We excluded such a discussion because we believe that the routine clinical use of biomarkers is not yet supported by existing data.Although not explicitly stated, we presume that Pramod and Singh intend to use procalcitonin to differentiate systemic inflammatory response syndrome due to an infection (sepsis) from cases due to noninfectious causes. For a biomarker to guide the treatment of sepsis, the test should have high sensitivity for early identification of those for whom antibiotics are not needed, provide high specificity for bacterial infection over other causes of the systemic inflammatory response syndrome, and accurately determine the response to therapy or need for continued antibiotics.Multiple assays are available to measure procalcitonin levels with various test-performance characteristics.3Schneider H.G. Lam Q.T. Procalcitonin for the clinical laboratory: a review.Pathology. 2007; 39: 383-390Crossref PubMed Scopus (149) Google Scholar The “gold standard” in evaluating these assays is often a positive blood culture—a result confounded by the administration of antibiotics and contamination by nonpathogenic species. In even the best cases, the sensitivity of any procalcitonin assay is <100%, making it impossible to exclude bacterial infections in the setting of suspected sepsis. Considering the increase in mortality attributable to delays in appropriate antibiotics,4Kumar A. Roberts D. Wood K.E. et al.Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock.Crit Care Med. 2006; 34: 1589-1596Crossref PubMed Scopus (4012) Google Scholar it would be difficult to justify withholding antibiotics in suspected sepsis on the basis of a procalcitonin level.Elevated procalcitonin levels are not specific for bacterial infections. High concentrations have been reported in systemic inflammatory response syndrome of noninfectious causes, autoimmune diseases, severe trauma, surgery, heat stroke, cardiogenic shock, and fungal and parasitic infections.5Muller B. Becker K.L. Procalcitonin: how a hormone became a marker and mediator of sepsis.Swiss Med Wkly. 2001; 131: 595-602PubMed Google Scholar, 6Mitaka C. Clinical laboratory differentiation of infectious versus non-infectious systemic inflammatory response syndrome.Clin Chim Acta. 2005; 351: 17-29Crossref PubMed Scopus (151) Google Scholar Therefore, an elevated procalcitonin level does not preclude the consideration of diagnoses other than bacterial sepsis.The most promising role for procalcitonin in sepsis management is the discontinuation of antibiotics in patients presenting initially with a suspected infection. A recent randomized controlled study attempted to use procalcitonin to safely reduce the duration of antibiotic therapy in severe sepsis and septic shock.7Nobre V. Harbarth S. Graf J.D. et al.Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial.Am J Respir Crit Care Med. 2008; 177: 498-505Crossref PubMed Scopus (480) Google Scholar This single-center study included only 79 of 282 (28%) eligible patients, and all received at least 3 days of antibiotics. The procalcitonin-guided cohort had a reduction in the duration of antibiotic treatment. However, mortality was numerically increased in those in the procalcitonin-guided arm. The study was underpowered to confidently exclude such small but potentially meaningful increases in mortality.With the multiplicity of treatments in severe sepsis and the rapidity with which they must be administered, research is clearly needed to determine how biomarkers, including procalcitonin, might improve clinical decision-making. Currently, we do not advocate their routine use for including or excluding bacterial causes of sepsis nor for guiding the duration of antibiotic therapy. Pramod and Singh1Pramod J. Singh A. Sepsis biomarkers.Am J Med. 2008; 121 (xx-xx)Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar question the omission of biomarkers, particularly procalcitonin, from our review of sepsis.2O'Brien Jr, J.M. Ali N.A. Aberegg S.K. Abraham E. Sepsis.Am J Med. 2007; 120: 1012-1022Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar They suggest that such biomarkers have a role in early detection and follow-up of septic patients. We excluded such a discussion because we believe that the routine clinical use of biomarkers is not yet supported by existing data. Although not explicitly stated, we presume that Pramod and Singh intend to use procalcitonin to differentiate systemic inflammatory response syndrome due to an infection (sepsis) from cases due to noninfectious causes. For a biomarker to guide the treatment of sepsis, the test should have high sensitivity for early identification of those for whom antibiotics are not needed, provide high specificity for bacterial infection over other causes of the systemic inflammatory response syndrome, and accurately determine the response to therapy or need for continued antibiotics. Multiple assays are available to measure procalcitonin levels with various test-performance characteristics.3Schneider H.G. Lam Q.T. Procalcitonin for the clinical laboratory: a review.Pathology. 2007; 39: 383-390Crossref PubMed Scopus (149) Google Scholar The “gold standard” in evaluating these assays is often a positive blood culture—a result confounded by the administration of antibiotics and contamination by nonpathogenic species. In even the best cases, the sensitivity of any procalcitonin assay is <100%, making it impossible to exclude bacterial infections in the setting of suspected sepsis. Considering the increase in mortality attributable to delays in appropriate antibiotics,4Kumar A. Roberts D. Wood K.E. et al.Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock.Crit Care Med. 2006; 34: 1589-1596Crossref PubMed Scopus (4012) Google Scholar it would be difficult to justify withholding antibiotics in suspected sepsis on the basis of a procalcitonin level. Elevated procalcitonin levels are not specific for bacterial infections. High concentrations have been reported in systemic inflammatory response syndrome of noninfectious causes, autoimmune diseases, severe trauma, surgery, heat stroke, cardiogenic shock, and fungal and parasitic infections.5Muller B. Becker K.L. Procalcitonin: how a hormone became a marker and mediator of sepsis.Swiss Med Wkly. 2001; 131: 595-602PubMed Google Scholar, 6Mitaka C. Clinical laboratory differentiation of infectious versus non-infectious systemic inflammatory response syndrome.Clin Chim Acta. 2005; 351: 17-29Crossref PubMed Scopus (151) Google Scholar Therefore, an elevated procalcitonin level does not preclude the consideration of diagnoses other than bacterial sepsis. The most promising role for procalcitonin in sepsis management is the discontinuation of antibiotics in patients presenting initially with a suspected infection. A recent randomized controlled study attempted to use procalcitonin to safely reduce the duration of antibiotic therapy in severe sepsis and septic shock.7Nobre V. Harbarth S. Graf J.D. et al.Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial.Am J Respir Crit Care Med. 2008; 177: 498-505Crossref PubMed Scopus (480) Google Scholar This single-center study included only 79 of 282 (28%) eligible patients, and all received at least 3 days of antibiotics. The procalcitonin-guided cohort had a reduction in the duration of antibiotic treatment. However, mortality was numerically increased in those in the procalcitonin-guided arm. The study was underpowered to confidently exclude such small but potentially meaningful increases in mortality. With the multiplicity of treatments in severe sepsis and the rapidity with which they must be administered, research is clearly needed to determine how biomarkers, including procalcitonin, might improve clinical decision-making. Currently, we do not advocate their routine use for including or excluding bacterial causes of sepsis nor for guiding the duration of antibiotic therapy. Sepsis BiomarkersThe American Journal of MedicineVol. 121Issue 6PreviewIn a review on sepsis by O'Brien et al,1 the discussants do not mention anything about the sepsis biomarkers, which have a role in the early detection and serial follow-up of patients with sepsis. Full-Text PDF