This was asked about in Question 9 from the second paper of 2009. Question 23 from the first paper of 2010 and the near-identical Question 6 from the second paper of 2016 ask specifically about procalcitonin, because it is the hot new thing.
One can find a plethora of articles on this topic, all unimaginatively titled "Biomarkers of sepsis":
In brief summary:
- ESR: cheap, easy, but unreliable, affected by age, temperature, lab technique, and is completely nonspecific for sepsis
- CRP: cheap, easy, but also elevated in non-infective situations eg. MI, burns, surgery, trauma, autoimmune disease - and not as specific as procalcitonin
- Procalcitonin: quick, more specific for bacterial sepsis than CRP, but expensive. For the discrimination of infectious from non-infectious cause of fever, the clinical judgement of an ED physician is at least equally accurate, if not better.
- Non-infective causes of PCt elevation: burns, massive tissue necrosis, tumour lysis, cardiac or major abdominal surgery, multi-organ system failure, ESRD, paraneoplastic production
- Important procalcitonin trials to mention:
- ProSEP(2008) - reduced antibiotic exposure
- ProSICU (2009) - reduced antibiotic exposure
- ProVAP (2009) - reduced antibiotic exposure (after VAP onset)
- ProRATA (2010) - reduced antibiotic exposure
- PASS (2013) - no improvement of survival, longer stay, worse organ function!
- SAPS (2016) - reduced antibiotic exposure, and improved 28-day survival (20% vs 25%)
- Other weird ones to remember:
- Pro-adrenomedullin, LPS-binding protein, sTREM-1, presepsin, HMGB-1, CD64
To make more detail available, the markers, their properties, advantages and disadvantages have been compiled into the table below. Where possible, references to the relevant publication are included. Elsewhere the main reference is Cho and Choi's review paper. If the time-poor exam candidate were to limit themselves to only one article, they could do much worse. Again, Oh's Manual is useless for this purpose; two paragraphs are devoted to biomarkers of sepsis on page 720 of the 7th edition (in Chapter 69 by De Gaudio).
Without further ado:
Marker | Physiology | Advantages | Disadvantages |
ESR |
|
|
|
CRP |
|
|
|
Procalcitonin |
|
|
|
Pro-
|
|
|
|
LPS-binding protein |
|
|
|
sTREM-1 |
|
|
|
Presepsin (sCD14-st) |
|
|
|
HMGB-1 |
|
|
|
CD64 |
|
|
|
The college loves procalcitonin. It has been the subject of Question 23 from the first paper of 2010 and the near-identical Question 6 from the second paper of 2016. The cancidates were asked to critically evaluate the use of procalcitonin, quoting some studies where possible. The answer to these questions is reproduced below to simplify revision:
Povoa, P., et al. "C-reactive protein as an indicator of sepsis." Intensive care medicine 24.10 (1998): 1052-1056.
Wacker, Christina, et al. "Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis." The Lancet infectious diseases 13.5 (2013): 426-435.
Opal, Steven M., et al. "Relationship between plasma levels of lipopolysaccharide (LPS) and LPS-binding protein in patients with severe sepsis and septic shock." Journal of Infectious Diseases 180.5 (1999): 1584-1589.
Shozushima, Tatsuyori, et al. "Usefulness of presepsin (sCD14-ST) measurements as a marker for the diagnosis and severity of sepsis that satisfied diagnostic criteria of systemic inflammatory response syndrome."Journal of Infection and Chemotherapy 17.6 (2011): 764-769.
Gámezâ€Díaz, Laura Y., et al. "Diagnostic Accuracy of HMGBâ€1, sTREMâ€1, and CD64 as Markers of Sepsis in Patients Recently Admitted to the Emergency Department." Academic Emergency Medicine 18.8 (2011): 807-815.
Kwofie, L., et al. "Evaluation of circulating soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) to predict risk profile, response to antimicrobial therapy, and development of complications in patients with chemotherapy-associated febrile neutropenia: a pilot study." Annals of hematology 91.4 (2012): 605-611.
Gros, Antoine, et al. "The sensitivity of neutrophil CD64 expression as a biomarker of bacterial infection is low in critically ill patients." Intensive care medicine 38.3 (2012): 445-452.
Gámezâ€Díaz, Laura Y., et al. "Diagnostic Accuracy of HMGBâ€1, sTREMâ€1, and CD64 as Markers of Sepsis in Patients Recently Admitted to the Emergency Department." Academic Emergency Medicine 18.8 (2011): 807-815.
Calfee, Carolyn S., and Jérôme Pugin. "The search for diagnostic markers in sepsis: many miles yet to go." American journal of respiratory and critical care medicine 186.1 (2012): 2-4.
Faix, James D. "Biomarkers of sepsis*." Critical reviews in clinical laboratory sciences 50.1 (2013): 23-36.
Singer, Mervyn. "Biomarkers in sepsis." Current opinion in pulmonary medicine19.3 (2013): 305.
Kibe, Savitri, Kate Adams, and Gavin Barlow. "Diagnostic and prognostic biomarkers of sepsis in critical care." Journal of antimicrobial chemotherapy66.suppl 2 (2011): ii33-ii40.
Henriquez-Camacho, Cesar, and Juan Losa. "Biomarkers for Sepsis." BioMed research international 2014 (2014).
Cho, Sung-Yeon, and Jung-Hyun Choi. "Biomarkers of sepsis." Infection & chemotherapy 46.1 (2014): 1-12.
Zacharski, Leo R., and Robert A. Kyle. "Significance of extreme elevation of erythrocyte sedimentation rate." Jama 202.4 (1967): 264-266.
BANNICK, EDWIN G., ROBERT O. GREGG, and CHESTER M. GUERNSEY. "The erythrocyte sedimentation rate: the adequacy of a simple test and its practical application in clinical medicine." Journal of the American Medical Association 109.16 (1937): 1257-1262.
Hameed, M. Amjad, and Sobia Waqas. "Physiological basis and clinical utility of erythrocyte sedimentation rate." Pak J Med Sci 2006; 22: p214 217 (2006).
Saadeh, Constantine, and Tex Amarillo. "The erythrocyte sedimentation rate: old and new clinical applications" South Med J. 1998 Mar;91(3):220-5.
Tillett, William S., and Thomas Francis. "Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus." The Journal of experimental medicine 52.4 (1930): 561-571.
Vincent, Jean-Louis, Katia Donadello, and Xavier Schmit. "Biomarkers in the critically ill patient: C-reactive protein." Critical care clinics 27.2 (2011): 241-251.
Povoa, P., et al. "Câ€reactive protein as a marker of infection in critically ill patients." Clinical microbiology and infection 11.2 (2005): 101-108.
Schmit, Xavier, and Jean Louis Vincent. "The time course of blood C-reactive protein concentrations in relation to the response to initial antimicrobial therapy in patients with sepsis." Infection 36.3 (2008): 213-219.
Kushner, I. R. V. I. N. G., and G. E. R. A. R. D. Feldmann. "Control of the acute phase response. Demonstration of C-reactive protein synthesis and secretion by hepatocytes during acute inflammation in the rabbit." The Journal of experimental medicine 148.2 (1978): 466-477.
Vigushin, David M., Mark B. Pepys, and Philip N. Hawkins. "Metabolic and scintigraphic studies of radioiodinated human C-reactive protein in health and disease." Journal of clinical investigation 91.4 (1993): 1351.
Maruna, P., K. Nedelnikova, and R. Gurlich. "Physiology and genetics of procalcitonin." Physiological Research 49 (2000): S57-S62.
Delevaux, I., et al. "Can procalcitonin measurement help in differentiating between bacterial infection and other kinds of inflammatory processes?."Annals of the rheumatic diseases 62.4 (2003): 337-340.
Maniaci, Vincenzo, et al. "Procalcitonin in young febrile infants for the detection of serious bacterial infections." Pediatrics 122.4 (2008): 701-710.
Becker, Kenneth L., Richard Snider, and Eric S. Nylen. "Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations."Critical care medicine 36.3 (2008): 941-952.
Limper, Maarten, et al. "The diagnostic role of procalcitonin and other biomarkers in discriminating infectious from non-infectious fever." Journal of Infection 60.6 (2010): 409-416.
Höflich, R. Sabat C., and W. D. Döcke. "Massive elevation of procalcitonin plasma levels in the absence of infection in kidney transplant patients treated with pan-T-cell antibodies." Intensive Care Med 27 (2001): 987-991.
Wacker, Christina, et al. "Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis." The Lancet infectious diseases 13.5 (2013): 426-435.
Hausfater, Pierre, et al. "Serum procalcitonin measurement as diagnostic and prognostic marker in febrile adult patients presenting to the emergency department." Critical Care 11.3 (2007): R60.
Bouadma, Lila, et al. "Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial." The Lancet 375.9713 (2010): 463-474.
Maruna, P., K. Nedelnikova, and R. Gurlich. "Physiology and genetics of procalcitonin." Physiological Research 49 (2000): S57-S62.
Assink-de Jong, Evelien, et al. "Stop Antibiotics on guidance of Procalcitonin Study (SAPS): a randomised prospective multicenter investigator-initiated trial to analyse whether daily measurements of procalcitonin versus a standard-of-care approach can safely shorten antibiotic duration in intensive care unit patients-calculated sample size: 1816 patients." BMC infectious diseases 13.1 (2013): 178.
Jensen, Jens-Ulrik, et al. "The Procalcitonin And Survival Study (PASS)–a randomised multi-center investigator-initiated trial to investigate whether daily measurements biomarker Procalcitonin and pro-active diagnostic and therapeutic responses to abnormal Procalcitonin levels, can improve survival in intensive care unit patients. Calculated sample size (target population): 1000 patients." BMC infectious diseases 8.1 (2008): 91.
Nobre, Vandack, et al. "Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial." American journal of respiratory and critical care medicine 177.5 (2008): 498.
Jensen, Jens U., et al. "Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: A randomized trial*." Critical care medicine 39.9 (2011): 2048-2058.
Hochreiter, Marcel, et al. "Procalcitonin to guide duration of antibiotic therapy in intensive care patients: a randomized prospective controlled trial." Crit Care13.3 (2009): R83.
Stolz, Daiana, et al. "Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study." European Respiratory Journal34.6 (2009): 1364-1375.
Hoeboer, Sandra H., et al. "The diagnostic accuracy of procalcitonin for bacteraemia: a systematic review and meta-analysis." Clinical Microbiology and Infection (2015).
Simon, Liliana, et al. "Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis." Clinical Infectious Diseases 39.2 (2004): 206-217.
Linscheid, Philippe, et al. "Autocrine/paracrine role of inflammation-mediated calcitonin gene-related peptide and adrenomedullin expression in human adipose tissue." Endocrinology 146.6 (2005): 2699-2708.
Christ-Crain, Mirjam, et al. "Mid-regional pro-adrenomedullin as a prognostic marker in sepsis: an observational study." Crit Care 9.6 (2005): R816-R824.
Al Shuaibi, Munirah, et al. "Pro-adrenomedullin as a novel biomarker for predicting infections and response to antimicrobials in febrile patients with hematologic malignancies." Clinical infectious diseases 56.7 (2013): 943-950.
Debiane, Labib, 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*." Critical care medicine 42.12 (2014): 2500-2507.
Cavallazzi, Rodrigo, et al. "Midregional proadrenomedullin for prognosis in community-acquired pneumonia: A systematic review." Respiratory medicine108.11 (2014): 1569-1580.
Zuur-Telgen, Maaike C., et al. "Stable-state midrange-proadrenomedullin level is a strong predictor of mortality in patients with COPD." CHEST Journal 145.3 (2014): 534-541.
Funke-Kaiser, Anne, et al. "Predictive value of midregional pro-adrenomedullin compared to natriuretic peptides for incident cardiovascular disease and heart failure in the population-based FINRISK 1997 cohort." Annals of medicine 46.3 (2014): 155-162.
Akpinar, Serdar, et al. "Performance evaluation of MR-proadrenomedullin and other scoring systems in severe sepsis with pneumonia." Journal of thoracic disease 6.7 (2014): 921.
Struck, Joachim, et al. "Identification of an adrenomedullin precursor fragment in plasma of sepsis patients." Peptides 25.8 (2004): 1369-1372.
Potocki, Mihael, Ronny Ziller, and Christian Mueller. "Mid-regional pro-adrenomedullin in acute heart failure: a better biomarker or just another biomarker?." Current heart failure reports 9.3 (2012): 244-251.
Jerala, Roman. "Structural biology of the LPS recognition." International Journal of Medical Microbiology 297.5 (2007): 353-363.
Choi, Jung Hyun, and Wan Shik Shin. Korean Journal of Infectious Diseases 32.2 (2000): 148-157."Pathogenesis of sepsis and concepts of immunotherapy."
Zweigner, Janine, et al. "High concentrations of lipopolysaccharide-binding protein in serum of patients with severe sepsis or septic shock inhibit the lipopolysaccharide response in human monocytes." Blood 98.13 (2001): 3800-3808.
Chen, Yi-Yuan, et al. "Lipopolysaccharide binding protein in cirrhotic patients with severe sepsis." Journal of the Chinese Medical Association 77.2 (2014): 68-74.
Gibot, Sébastien. "Clinical review: role of triggering receptor expressed on myeloid cells-1 during sepsis." CRITICAL CARE-LONDON- 9.5 (2005): 485.
Gibot, Sébastien, et al. "Plasma level of a triggering receptor expressed on myeloid cells-1: its diagnostic accuracy in patients with suspected sepsis."Annals of Internal Medicine 141.1 (2004): 9-15.
Jiyong, Jing, et al. "Diagnostic value of the soluble triggering receptor expressed on myeloid cells-1 in bacterial infection: a meta-analysis." Intensive care medicine 35.4 (2009): 587-595.
Wu, Youping, et al. "Accuracy of plasma sTREM-1 for sepsis diagnosis in systemic inflammatory patients: a systematic review and meta-analysis." Crit Care 16.6 (2012): R229.
Jeong, Su Jin, et al. "Measurement of plasma sTREM-1 in patients with severe sepsis receiving early goal-directed therapy and evaluation of its usefulness."Shock 37.6 (2012): 574-578.
Oufella, Hafid Ait, et al. "Circulating Levels of sTREM-1 and Mortality in Patients With an Acute Myocardial Infarction." Circulation 130.Suppl 2 (2014): A16204-A16204.
Endo, Shigeatsu, et al. "Usefulness of presepsin in the diagnosis of sepsis in a multicenter prospective study." Journal of Infection and Chemotherapy 18.6 (2012): 891-897.
Olad, Elham, et al. "Presepsin (Scd14) as a Marker of Serious Bacterial Infections in Chemotherapy Induced Severe Neutropenia." Iranian Journal of Pediatrics 24.6 (2014): 715-722.
Ulla, Marco, et al. "Diagnostic and prognostic value of presepsin in the management of sepsis in the emergency department: a multicenter prospective study." Crit Care 17.4 (2013): R168.
Masson, Serge, et al. "Presepsin (soluble CD14 subtype) and procalcitonin levels for mortality prediction in sepsis: data from the Albumin Italian Outcome Sepsis trial." Crit Care 18.1 (2014): R6.
Ramana, K. V., et al. "Presepsin: A Novel and Potential Diagnostic Biomarker for Sepsis." American Journal of Medical and Biological Research 2.4 (2014): 97-100.
Madenci, Özlem Çakır, et al. "Evaluation of soluble CD14 subtype (presepsin) in burn sepsis." Burns 40.4 (2014): 664-669.
Gibot, Sébastien, et al. "High-mobility group box 1 protein plasma concentrations during septic shock." Intensive care medicine 33.8 (2007): 1347-1353.
Sundén-Cullberg, Jonas, et al. "Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock*." Critical care medicine 33.3 (2005): 564-573.
Klune, John R., et al. "HMGB1: endogenous danger signaling." Molecular Medicine 14.7-8 (2008): 476.
Icardi, M., et al. "CD64 index provides simple and predictive testing for detection and monitoring of sepsis and bacterial infection in hospital patients."Journal of clinical microbiology 47.12 (2009): 3914-3919.
Cid, Joan, et al. "Neutrophil CD64: diagnostic accuracy and prognostic value in patients presenting to the emergency department." European journal of clinical microbiology & infectious diseases 30.7 (2011): 845-852.
Cid, Joan, et al. "Neutrophil CD64 expression as marker of bacterial infection: a systematic review and meta-analysis." Journal of Infection 60.5 (2010): 313-319.
Jensen, Jens U., et al. "Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial." Critical care medicine 39.9 (2011): 2048-2058.
de Jong, Evelien, et al. "Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial." The Lancet Infectious Diseases(2016).
Hoeboer, Sandra H., et al. "The diagnostic accuracy of procalcitonin for bacteraemia: a systematic review and meta-analysis." Clinical Microbiology and Infection 21.5 (2015): 474-481.
Zhou, George, and Kwok M. Ho. "Procalcitonin concentrations as a predictor of unexpected readmission and mortality after intensive care unit discharge: A retrospective cohort study." Journal of critical care 33 (2016): 240-244.
Shehabi, Yahya, et al. "Procalcitonin algorithm in critically ill adults with undifferentiated infection or suspected sepsis. A randomized controlled trial." American journal of respiratory and critical care medicine 190.10 (2014): 1102-1110.
Matsumura, Yosuke, et al. "Serum procalcitonin level and SOFA score at discharge from the intensive care unit predict post-intensive care unit mortality: a prospective study." PloS one 9.12 (2014): e114007.
Azevedo, José Raimundo Araujo de, et al. "Procalcitonin as a prognostic biomarker of severe sepsis and septic shock." Revista do Colégio Brasileiro de Cirurgiões 39.6 (2012): 456-461.
Hatherill, Mark, et al. "Procalcitonin and cytokine levels: relationship to organ failure and mortality in pediatric septic shock." Critical care medicine 28.7 (2000): 2591-2594.
Wacker, Christina, et al. "Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis." The Lancet infectious diseases 13.5 (2013): 426-435.
Meynaar, Iwan A., et al. "In critically ill patients, serum procalcitonin is more useful in differentiating between sepsis and SIRS than CRP, Il-6, or LBP." Critical care research and practice 2011 (2011).
Simon, Liliana, et al. "Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis." Clinical Infectious Diseases 39.2 (2004): 206-217.