Diagnosing sepsis - The role of laboratory medicine.

Sepsis is the host response to microbial pathogens resulting in significant morbidity and mortality. An accurate and timely diagnosis of sepsis allows prompt and appropriate treatment. This review discusses laboratory testing for sepsis because differentiating systemic inflammation from infection is challenging. Procalcitonin (PCT) is currently an FDA approved test to aid in the diagnosis of sepsis but with questionable efficacy. However, studies support the use of PCT for antibiotic de-escalation. Serial lactate measurements have been recommended for monitoring treatment efficacy as part of sepsis bundles. The 2016 sepsis consensus definitions include lactate concentrations >2mmol/L (>18mg/dL) as part of the definition of septic shock. Also included in the 2016 definitions are measuring bilirubin and creatinine to determine progression of organ failure indicating worse prognosis. Hematologic parameters, including a simple white blood cell count and differential, are frequently part of the initial sepsis diagnostic protocols. Several new biomarkers have been proposed to diagnose sepsis or to predict mortality, but they currently lack sufficient sensitivity and specificity to be considered as stand-alone testing. If sepsis is suspected, new technologies and microbiologic assays allow rapid and specific identification of pathogens. In 2016 there is no single laboratory test that accurately diagnoses sepsis.

[1]  Ash A. Alizadeh,et al.  Stereotyped and specific gene expression programs in human innate immune responses to bacteria , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Liqiong Yao,et al.  Higher serum level of myoglobin could predict more severity and poor outcome for patients with sepsis. , 2016, The American journal of emergency medicine.

[3]  S. Lemeshow,et al.  Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study. , 2015, Critical care medicine.

[4]  W. Fan,et al.  N-terminal pro-brain natriuretic peptide and cardiac troponin I for the prognostic utility in elderly patients with severe sepsis or septic shock in intensive care unit: A retrospective study. , 2015, Journal of critical care.

[5]  Dechang Chen,et al.  Serum procalcitonin and interleukin-6 levels may help to differentiate systemic inflammatory response of infectious and non-infectious origin. , 2003, Chinese medical journal.

[6]  M. Clementi,et al.  The Era of Molecular and Other Non-Culture-Based Methods in Diagnosis of Sepsis , 2010, Clinical Microbiology Reviews.

[7]  H. Wong,et al.  Interleukin-8 as a stratification tool for interventional trials involving pediatric septic shock. , 2008, American journal of respiratory and critical care medicine.

[8]  J. Katajisto,et al.  Febrile infection changes the expression of IgG Fc receptors and complement receptors in human neutrophils in vivo , 1997, Clinical and experimental immunology.

[9]  H. M. Soliman,et al.  C-reactive protein levels correlate with mortality and organ failure in critically ill patients. , 2003, Chest.

[10]  Jeffrey S Gerber,et al.  Combined biomarkers discriminate a low likelihood of bacterial infection among surgical intensive care unit patients with suspected sepsis. , 2016, Diagnostic microbiology and infectious disease.

[11]  E. Brody,et al.  Sepsis, oxidative stress, and hypoxia: Are there clues to better treatment? , 2015, Redox report : communications in free radical research.

[12]  L. Armstrong A Prospective Multicenter Derivation of a Biomarker Panel to Assess Risk of Organ Dysfunction, Shock, and Death in Emergency Department Patients with Suspected Sepsis , 2009 .

[13]  G. Tognoni,et al.  Circulating presepsin (soluble CD14 subtype) as a marker of host response in patients with severe sepsis or septic shock: data from the multicenter, randomized ALBIOS trial , 2015, Intensive Care Medicine.

[14]  L. M. Srivastava,et al.  Procalcitonin as a rapid diagnostic biomarker to differentiate between culture-negative bacterial sepsis and systemic inflammatory response syndrome: a prospective, observational, cohort study. , 2015, Journal of critical care.

[15]  J. Vincent,et al.  The Time Course of Blood C-reactive Protein Concentrations in Relation to the Response to Initial Antimicrobial Therapy in Patients with Sepsis , 2008, Infection.

[16]  Geoff Bellingan,et al.  Sepsis biomarkers. , 2015, Clinica chimica acta; international journal of clinical chemistry.

[17]  Peter Schlattmann,et al.  Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. , 2013, The Lancet. Infectious diseases.

[18]  Ying Jiang,et al.  The Utility of Proadrenomedullin and Procalcitonin in Comparison to C-Reactive Protein as Predictors of Sepsis and Bloodstream Infections in Critically Ill Patients With Cancer* , 2014, Critical care medicine.

[19]  R. Chamberlain,et al.  The efficacy of procalcitonin as a biomarker in the management of sepsis: slaying dragons or tilting at windmills? , 2013, Surgical infections.

[20]  P. L. Petersen,et al.  Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: A randomized trial* , 2011, Critical care medicine.

[21]  Comprehensive Interpretation of Central Venous Oxygen Saturation and Blood Lactate Levels During Resuscitation of Patients With Severe Sepsis and Septic Shock in the Emergency Department , 2016, Shock.

[22]  K. Garey,et al.  Comparison of the T2Dx instrument with T2Candida assay and automated blood culture in the detection of Candida species using seeded blood samples. , 2013, Diagnostic microbiology and infectious disease.

[23]  A. A. Abou Tayoun,et al.  Democratizing molecular diagnostics for the developing world. , 2014, American journal of clinical pathology.

[24]  Adil Rafiq Rather,et al.  The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) , 2015 .

[25]  C. Sprung,et al.  Sepsis in European intensive care units: Results of the SOAP study* , 2006, Critical care medicine.

[26]  P. Póvoa,et al.  C-reactive protein as a marker of infection in critically ill patients. , 2005, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[27]  Jessica Brooks,et al.  Understanding the Inflammatory Cytokine Response in Pneumonia and Sepsis , 2008 .

[28]  A. Ingsathit,et al.  Lactate and combined parameters for triaging sepsis patients into intensive care facilities. , 2016, Journal of critical care.

[29]  D. Angus,et al.  Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. , 2016, American journal of respiratory and critical care medicine.

[30]  Larry A Nathanson,et al.  Serum lactate as a predictor of mortality in emergency department patients with infection. , 2005, Annals of emergency medicine.

[31]  P. Parsons,et al.  Plasma interleukin-8 is not an effective risk stratification tool for adults with vasopressor-dependent septic shock* , 2010, Critical care medicine.

[32]  S. Shulman,et al.  Rapid Identification of Pathogens from Pediatric Blood Cultures by Use of the FilmArray Blood Culture Identification Panel , 2014, Journal of Clinical Microbiology.

[33]  Aseem Kumar,et al.  Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: A randomized trial , 2012 .

[34]  C. Sprung,et al.  Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012 , 2013, Intensive Care Medicine.

[35]  D. Andersson,et al.  A General Method for Rapid Determination of Antibiotic Susceptibility and Species in Bacterial Infections , 2014, Journal of Clinical Microbiology.

[36]  H. Ni,et al.  C-Reactive Protein as a Predictor of Mortality in Critically Ill Patients: A Meta-Analysis and Systematic Review , 2011, Anaesthesia and intensive care.

[37]  Alain Cariou,et al.  Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569] , 2004, Critical care.

[38]  P. Póvoa,et al.  Early identification of intensive care unit-acquired infections with daily monitoring of C-reactive protein: a prospective observational study , 2006, Critical care.

[39]  K. Wood,et al.  Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock* , 2006, Critical care medicine.

[40]  D. Aujesky,et al.  Biomarker-guided personalised emergency medicine for all - hope for another hype? , 2015, Swiss medical weekly.

[41]  M. Donnino,et al.  Etiology and therapeutic approach to elevated lactate levels. , 2013, Mayo Clinic proceedings.

[42]  Leif E. Peterson,et al.  Integrating rapid pathogen identification and antimicrobial stewardship significantly decreases hospital costs. , 2013, Archives of pathology & laboratory medicine.

[43]  S. Grabherr,et al.  Elevation of NT-proBNP and cardiac troponins in sepsis-related deaths: a forensic perspective , 2016, International Journal of Legal Medicine.

[44]  W. Knaus,et al.  Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. , 1992, Chest.

[45]  S. Barghouthi A Universal Method for the Identification of Bacteria Based on General PCR Primers , 2011, Indian Journal of Microbiology.

[46]  George Scott,et al.  Toward resolving the challenges of sepsis diagnosis. , 2004, Clinical chemistry.

[47]  T. Fok,et al.  Neutrophil CD64 Expression: A Sensitive Diagnostic Marker for Late-Onset Nosocomial Infection in Very Low Birthweight Infants , 2002, Pediatric Research.

[48]  D. Otten Albumin Replacement in Patients with Severe Sepsis or Septic Shock , 2014 .

[49]  R. Seemann,et al.  Increased plasma vaspin concentration in patients with sepsis: an exploratory examination , 2015, Biochemia medica.

[50]  K. Petroni,et al.  Modulation of human polymorphonuclear leukocyte IgG Fc receptors and Fc receptor-mediated functions by IFN-gamma and glucocorticoids. , 1988, Journal of immunology.

[51]  J. Vincent,et al.  Procalcitonin used as a marker of infection in the intensive care unit. , 1999, Critical care medicine.

[52]  J. Maurer Procalcitonin Algorithms for Antibiotic Therapy Decisions: A Systematic Review of Randomized Controlled Trials and Recommendations for Clinical Algorithms , 2012 .

[53]  A. Gordon,et al.  Monocyte Tumor Necrosis Factor-α–Converting Enzyme Catalytic Activity and Substrate Shedding in Sepsis and Noninfectious Systemic Inflammation* , 2015, Critical care medicine.

[54]  B. Davis,et al.  Comparison of neutrophil CD64 expression, manual myeloid immaturity counts, and automated hematology analyzer flags as indicators of infection or sepsis. , 2005, Laboratory hematology : official publication of the International Society for Laboratory Hematology.

[55]  Munish Goyal,et al.  Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock* , 2009, Critical care medicine.

[56]  Zijlstra,et al.  Levels of soluble FcγRIII correlate with disease severity in sepsis , 1998, Clinical and experimental immunology.

[57]  A. Ihan,et al.  Neutrophil and Monocyte CD64 and CD163 Expression in Critically Ill Neonates and Children with Sepsis: Comparison of Fluorescence Intensities and Calculated Indexes , 2008, Mediators of inflammation.

[58]  R. Wenzel,et al.  Managing antibiotic resistance. , 2000, The New England journal of medicine.

[59]  Christian Trautwein,et al.  Circulating MicroRNAs as Biomarkers for Sepsis , 2016, International journal of molecular sciences.

[60]  K. Reinhart,et al.  Rapid diagnosis of sepsis , 2013, Virulence.

[61]  P. Schuetz,et al.  The prognostic blood biomarker proadrenomedullin for outcome prediction in patients with chronic obstructive pulmonary disease (COPD): a qualitative clinical review , 2015, Clinical chemistry and laboratory medicine.

[62]  S. Zanotti,et al.  Severe Sepsis and Septic Shock , 2011 .

[63]  E. Wenzler,et al.  Controversies in Antimicrobial Stewardship: Focus on New Rapid Diagnostic Technologies and Antimicrobials , 2016, Antibiotics.

[64]  D. Ecker,et al.  Improved Sensitivity for Molecular Detection of Bacterial and Candida Infections in Blood , 2014, Journal of Clinical Microbiology.

[65]  Purvesh Khatri,et al.  A comprehensive time-course–based multicohort analysis of sepsis and sterile inflammation reveals a robust diagnostic gene set , 2015, Science Translational Medicine.

[66]  S. Resino,et al.  A combined score of pro- and anti-inflammatory interleukins improves mortality prediction in severe sepsis. , 2012, Cytokine.

[67]  O. Liesenfeld,et al.  Molecular diagnosis of sepsis: New aspects and recent developments. , 2014, European journal of microbiology & immunology.

[68]  G. Tognoni,et al.  Sequential N-Terminal Pro-B-Type Natriuretic Peptide and High-Sensitivity Cardiac Troponin Measurements During Albumin Replacement in Patients With Severe Sepsis or Septic Shock* , 2015, Critical care medicine.

[69]  J. Losa,et al.  Biomarkers for Sepsis , 2014, BioMed research international.

[70]  C. Wojewoda Pathology consultation on matrix-assisted laser desorption ionization-time of flight mass spectrometry for microbiology. , 2013, American journal of clinical pathology.

[71]  Alexandru Florin Rogobete,et al.  Use of miRNAs as Biomarkers in Sepsis , 2015, Analytical cellular pathology.

[72]  Amit Arora,et al.  Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry: a Fundamental Shift in the Routine Practice of Clinical Microbiology , 2013, Clinical Microbiology Reviews.

[73]  M. Safar,et al.  Diagnosis and follow-up of infections in intensive care patients: value of C-reactive protein compared with other clinical and biological variables. , 2002, Critical care medicine.

[74]  Jeffrey L. Dantzler,et al.  Cutting Edge: Identification of Neutrophil PGLYRP1 as a Ligand for TREM-1 , 2015, The Journal of Immunology.

[75]  J. A. Quayle,et al.  Neutrophils from the synovial fluid of patients with rheumatoid arthritis express the high affinity immunoglobulin G receptor, FcγRI (CD64): role of immune complexes and cytokines in induction of receptor expression , 1997, Immunology.

[76]  M. Levy,et al.  Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008 , 2007, Intensive Care Medicine.

[77]  M. Christ-Crain,et al.  Long-term Prognosis in COPD Exacerbation: Role of Biomarkers, Clinical Variables and Exacerbation Type , 2015, COPD.

[78]  R. Weissleder,et al.  Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis , 2015, Science.

[79]  N. Miller,et al.  Assessment of Impact of Peptide Nucleic Acid Fluorescence In Situ Hybridization for Rapid Identification of Coagulase-Negative Staphylococci in the Absence of Antimicrobial Stewardship Intervention , 2011, Journal of Clinical Microbiology.

[80]  Daniel Talmor,et al.  Occult hypoperfusion and mortality in patients with suspected infection , 2007, Intensive Care Medicine.

[81]  John A Kellum,et al.  Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. , 2007, Archives of internal medicine.

[82]  T. Pearson,et al.  Blood polymorphonuclear leukocytes from the majority of sickle cell patients in the crisis phase of the disease show enhanced adhesion to vascular endothelium and increased expression of CD64. , 1998, Blood.

[83]  R. Paladini,et al.  Procalcitonin, C-reactive protein, white blood cells and SOFA score in ICU: diagnosis and monitoring of sepsis. , 2006, Minerva anestesiologica.

[84]  V. A. Gant,et al.  Increased distribution and expression of CD64 on blood polymorphonuclear cells from patients with the systemic inflammatory response syndrome (SIRS) , 2001, Clinical and experimental immunology.