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:
  • 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:

A Comparison among Laboratory Markers of Sepsis
Marker Physiology Advantages Disadvantages

ESR

  • Erythrocyte sedimentation rate; the rate at which EDTA-treated diluted RBCs clump together in a vertical test tube.
  • Elevated in inflammatory conditions, mainly because of the increased amount of fibrinogen, which is an acute phase reactant
  • Takes about one hour to perform
  • Completely non-specific
  • Old-school: as sophistication of laboratories has increased, the demand for ESR testing has diminished
  • Varies with age, temperature, test tube position... Unreliable
  • Non-infectious causes of elevation:
    • Malignancy (eg. multiple myeloma)
    • Inflammatory disease, eg. RA/PMR
    • Chronic renal failure
    • Vasculitis, eg. temporal arteritis

CRP

  • A nonspecific marker of inflammation
  • Non-infectious causes of elevation:
    • Surgery, trauma
    • Burns
    • Myocardial infarctions
    • Rheumatological disease
  • Unreliable in patients with a dysfunctional liver
  • Not as good as procalcitonin in discriminating infectious from non-infectious causes of fever -Pct vs. CRP meta-analysis (2004)

Procalcitonin

  • The prohormone of calcitonin, normally synthesised by the C-cells of the thyroid gland, but produced ectopically by neuroendocrine cells in the lung and intestine in the context of sepsis.
  • 116-peptide molecule, 13 kDa
  • Cleared by the parathyroid gland; its renal clearance is minimal.
  • Synthesis is triggered by bacterial endotoxin and inflammatory cytokines.
  • Levels peak after 6 hours.
  • It has a half-life of 24-36 hours
  • Expensive
  • Optimal use requires serial measurements, which is even more expensive.
  • No value in assessment of fungal or viral infections
  • No value in assessment of localised infections without a systemic response
  • There is disagreement as to what the negative cutoff value should be.
  • 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 elevation:
    • Burns
    • Massive tissue necrosis
    • Tumour lysis
    • Cardiac or major abdominal surgery
    • Multi-organ system failure
    • Treatment with T-cell antibodies
    • End-stage renal failure (procalcitonin is chronically elevated)
    • Paraneoplastic production, eg. by medullary thyroid carcinoma or by small-cell lung cancer

Pro-
adrenomedullin

LPS-binding protein

sTREM-1

Presepsin (sCD14-st)

  • Presepsin is a 13kDa protein, the the soluble N-terminal fragment of CD14 (a part of the LPS receptor from myeloid cells)
  • During inflammation, plasma protease activity generates these CD14 fragments.
  • Increases at 2 hours post insult, and has a half-life of 4-5 hours
  • Expensive
  • Not widely available
  • Promising literature, but still very little of it; wide acceptance has not been gained.
  • Enthusiasm among researchers may have the effect of obscuring the potential disadvantages
  • Elevated in non-septic patients:
    • Neutropenic mucositis
    • Hepatitis (chronic HepB)
    • Febrile but culture-negative patients
    • Psoriasis
  • Levels did not seem to increase in UTI
  • Affected by antimyeloid drugs: lower levels are seen after chemotherapy

HMGB-1

  • High-mobility group box 1 protein: a cytoplasmic and nuclear protein released by activated monocytes or necrotic tissues.
  • Undetectable in healthy subjects
  • Rises at 8-12 hours
  • Plateaus after 18-32 hours
  • Expensive
  • Not widely available
  • It may be a nonspecific "danger signal" rather than a sepsis-specific marker.
  • May also be elevated in malignancy and non-infectious inflammatory states, such as colitis, SLE, arthritis, radiation injury and ischaemia.

CD64

  • A membrane glycoprotein expressed on the surface of activated neutrophils
  • Expression increases hours after activation of innate immunity
  • Not expressed by normal neutrophils
  • Expensive
  • Not widely available
  • Not a soluble mediator; requires some neutrophils for testing (may be tricky in neutropenia)
  • All published studies thus far have suffered from poor methodology.

Procalcitonin in detail

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:

  • Introduction / definition:
    • Procalcitonin is the prohormone of calcitonin, normally synthesised by the C-cells of the thyroid gland, but produced ectopically by lung and intestine in the context of sepsis. As such, it is an attractive biomarker, and has been the subject of interesting research.
  • Rationale:
  • Evidence: what the recent trials say
  • Advantages
    • Quick to perform the assay
    • More specific for bacterial sepsis than CRP
    • Getting cheaper
    • Predictor of outcome - high levels associated with higher mortality and unexpected ICU readmission (Zhou et al, 2016)
    • Persistently high levels are associated with worse organ dysfunction (Hatherill et al, 2000 - as well as many other studies which confirmed this association)
    • Guides antibiotic therapy in the absence of better guesses (eg. where infectious diseases physicians are not available for an opinion)
    • Accurate in identifying bacterial sepsis -a meta-analysis by Wacker et al (2013) found an AUROC of 0.85, and Meynaar et al (2011) found a positive predictive value of 88%.
    • Better than CRP for bacterial sepsis (higher sensitivity, similar specificity - Simon et al, 2004)
  • Disadvantages
    • Expensive
    • Optimal use requires serial measurements, which is even more expensive.
    • Confounded by non-infectious conditions, such as...
      • Extreme inflammatory stimuli:
        • Burns
        • Massive tissue necrosis
        • Tumour lysis
        • Cardiac or major abdominal surgery
        • Multi-organ system failure
      • Treatment with T-cell antibodies
      • End-stage renal failure (procalcitonin is chronically elevated)
    • No value in assessment of fungal or viral infections
    • No value in assessment of localised infections without a systemic response
    • There is disagreement as to what the negative cutoff value should be.
    • 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.

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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.

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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.

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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.

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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.