Biomarkers of sepsis

By Alex Yartsev - 13/07/2015

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 7^th 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	Easy to perform. Requires no special equipment, and minimal technical skill Uses widely available cheap reagents. Available in resource-poor environments.	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	C-reactive protein is the protein responsible for precipitating C-polysaccharide during the acute phase of Streptococcus pneumonia infection. Molecular mass ~ 115 kDa Produced by the liver Its role is as an opsonin; it binds to soluble or particulate ligands and activates complement. Macrophages also have CRP receptors. CRP increases 4-6hrs after the start of an infection and then doubles every 8 hours, reaching a peak at 36-50 hours Half-life of 19 hours	Cheap Easy to perform Widely available As a marker for bacterial infections: Sensitivity 68-92% Specificity 40-67% Correlates with severity of infection A rapid decrease in CRP levels can be interpreted as a good response to antibiotic therapy	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	Useful in early identifying occult infection; levels peak rapidly after the first appearance of endotoxin, i.e. before blood cultures have time to incubate. Useful in discriminating between bacterial and non-infectious causes of inflammation, as its synthesis is triggered by bacterial endotoxin. Quick to perform More specific for bacterial sepsis than CRP. The strong industry stimulus behind the use of procalcitonin has resulted in a massive number of trials: Pct vs. CRP meta-analysis (2004) ProSEP study (2008) PASS study (2013) ProSICU study (2009) ProVAP study (2009) ProRATA study (2010) SAPS study (2016) Recent meta-analysis (2015)	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	Proadrenomedullin is the stable and physiologically inert mid-regional peptide fragment cleaved from the same precursor molecule as adrenomedullin. Adrenomedullin (ADM) is produced during physiological stress; roles include vasodilation, anti-inflammatory and antimicrobial effects. In fact it is a very potent vasodilator. It is produced by a variety of tissues: brain, lungs, heart, kidneys, endothelial cells and adipocytes. ADM is rapidly cleared from the circulation (half-life of 22 minutes) but proADM has a longer half-life. Proadrenomedullin mid-range fragment is present in the bloodstream in stoichiometrically equivalent amounts to ADM.	ProADM is higher in patients with sepsis than with SIRS In febrile neutropenia patients, proADM can distinguish sepsis from non-infectious SIRS Unlike procalcitonin, proADM rises in localised infectious processes (eg. abscesses) Also it seems to be superior to procalcitonin as a predictor of bloodstream infection, and of non-response to therapy ProADM predicts mortality in patients with community-acquired pneumonia and COPD; at least in some of the studies	Expensive Not widely available Levels do not seem to correlate very strongly with severity Non infectious causes of elevation: Congestive heart failure Acute heart failure
LPS-binding protein	A polypeptide that binds LPS Catalyses the transfer of LPS to the CD14 marker (a part of the monocyte cellular receptor for LPS) Mainly synthesized in the liver. Modulates the immune response Has a dual action, enhancing and inhibiting LPS signaling at low and higher levels, respectively.	Levels rise severalfold in sepsis, making LBP a useful diagnostic marker of sepsis	Expensive Not widely available LPS and LBP levels are affected by administration of antibiotics and generally do not correlate to the clinical course of sepsis. Affected by hepatic health, and in unexpected ways; for instance in cirrhotic patients higher LBP levels are actually associated with increased survival.
sTREM-1	Soluble triggering receptor expressed on myeloid cell 1 A soluble form of TREM-1, a glycopeptide receptor expressed on the surface of myeloid cells. Expression of sTREM-1 increases in bacterial and fungal sepsis	Probably as accurate as procalcitonin (if not better at a high cut-off) in the diagnosis of bacterial sepsis For bacterial infections: Sensitivity 82% Specificity 86% Admission sTREM-1 levels are independently associated with mortality Rapid decrease of sTREM-1 is associated with a better outcome	Expensive Not widely available A more recent meta-analysis has down-estimated its sensitivity and specificity Also elevated in acute MI Assay method significantly affects accuracy
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	Detects both systemic and localised bacterial infections: Sensitivity 87.8% Specificity 81.4% Rises very early: useful for early (emergency department) diagnosis of sepsis Prognostically important: evolution of presepsin levels was associated with outcome in the ALBIOS study Unlike procalcitonin, presepsin is not confused by the presence of severe burns Even though it is derived from WCCs, neutropenic patients still mount a high presepsin level in the presence of sepsis	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	HMGB-1 measurements on day 3 discriminated survivors from non-survivors with a sensitivity of 66% and specificity of 67% Correlates well with sepsis severity and degree of organ failure	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	Predicts positive blood cultures Predicts bacterial infection in febrile patients with a sensitivity of 87% A meta abalysis of (poor quality) studies suggests that it is a useful marker of bacterial infection: Sensitivity 79% Specificity 91%	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:
- Procalcitonin may be useful in identifying occult infection; levels peak within 6-8 hours after the first appearance of endotoxin, and this it may identify patients with severe infection before blood cultures have time to incubate, and before more serious manifestations of sepsis have time to evolve.
- Procalcitonin may be useful in discriminating between bacterial and non-infectious causes of inflammation, as its synthesis is triggered by bacterial endotoxin
Evidence: what the recent trials say
- The college answer usually quotes the PRORATA study which suggested that the use of procalcitonin could result in reduced antibiotic exposure.
- There are others:
- Overall, according to a recent meta-analysis by Hoeboer et al (2015, quoted by the college in their answer to Question 6 from the second paper of 2016)
  - "The optimal and most widely used procalcitonin cut-off value was 0.5 ng/mL with a corresponding sensitivity of 76% and specificity of 69%"
  - The authors concluded that procalcitonin had a "fair" diagnostic accuracy for bacteraemia.
  - According to an old meta-analysis (2004), it was more sensitive and more specific than CRP.
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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