Question 6

College answer

Introductory statement

• PCT is the pro-peptide of calcitonin, produced by the parafollicular cells of the thyroid and neuroendocrine cells of lung and intestine, and has been studied as a sepsis biomarker to help with the diagnosis/exclusion of sepsis and to guide the time course of antibiotic therapy

Rationale

• PCT is secreted in low concentrations in health (plasma level <0.1 ng/ml)
• Rises in response to pro-inflammatory stimulus, especially of bacterial origin, mostly from neuroendocrine cells of lungs and intestine
• Lag time of 2 – 4 hours after onset of sepsis, peaking at 24 – 36 hours
• Does not rise significantly with viral and non-infectious inflammations
• To exclude sepsis a cut-off plasma level of ≤ 0.2 ng/ml is used with levels ≥0.5 ng/ml suggesting sepsis
• Circulating levels halve daily when the infection is controlled

Advantages

• Theoretical use for diagnosis of bacterial infections, differential diagnosis of inflammatory response  Predictor of outcome – high levels correlate with organ dysfunction and persistently high levels associated with higher mortality
• Correlation with extent and severity of bacterial infections
• Guide duration of antibiotic therapy
• Faster response than waiting for incubation of blood cultures
• Better at discriminating sepsis from SIRS than CRP or cytokines
• Better diagnostic marker of bacterial sepsis than CRP
• Relatively cheap although more expensive than CRP

Disadvantages

• Increases in non-septic inflammatory conditions with massive necrosis e.g. major trauma, tumour lysis, cardiogenic shock and case report of massive amphetamine overdose
• Not useful for identifying viral or fungal infections or localised infections without systemic involvement
• May not be elevated in immunocompromised
• Serial measurements needed with added cost
• May be no better than experienced clinician in differentiating infectious from non-infectious cause of fever
•  

Evidence

• Conflicting

• Meta-analysis – Hoeboer et al 2015
•             Approx. 60 studies
•             Concluded low PCT values could be used to rule out bacteraemia
• Further studies needed on safety and efficacy of PCT as single diagnostic tool
•  
• Studies using PCT algorithms to guide duration of therapy
• PRORATA
•             Multi-centre RCT approx. 600 patients
•             No difference in outcome but PCT algorithm group used fewer antibiotics 
• ProGUARD
•             Used lower level of PCT for initiation and cessation of antibiotics  No difference between 2 arms on antibiotic duration
•  
• PASS
•             Danish multi-centre RCT with 1200 patients
•             Use of PCT algorithm for escalation of antibiotic therapy 
•             Did not improve survival
•          Associated with more organ failure and longer ICU stay
•  
• SAPS – Lancet 2016
•              Dutch study with approx. 1600 patients
•             Used PCT guided algorithm
•             Found reduction in antibiotic use and mortality benefit

Summary Statement For example:

• The evidence for the efficacy of PCT as a biomarker in sepsis is conflicting. Low values may be helpful in ruling out bacterial infection. Some studies show a benefit in using PCT algorithms to guide antibiotic therapy duration. In my practice I use PCT levels as a biomarker of sepsis judiciously in conjunction with careful clinical assessment and other elements of antibiotic stewardship on a caseby-case basis.

An acceptable answer addressed the following:

• Rationale for the use of PCT
• Pros and cons
• Some reference to the evidence
• Statement of candidate‟s own practice

Additional Examiners‟ Comments:

Most candidates were extremely vague and failed to deliver specific information. While often times the information provided was at least partially correct it was very non-specific and more in keeping with general comment rather than the knowledge expected of a specialist. Very few candidates demonstrated even a passing knowledge of the relevant literature.

Discussion

This question is in many ways identical to Question 23 from the first paper of 2010.

The discussion section was copy-pasted 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:
    • ProSEP study (2008)
    • PASS study (2008)
    • ProSICU study (2009)
    • ProVAP study (2009)
    • ProRATA study (2010)
    • ProGUARD study (2014)
    • SAPS study (2016)
  • 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.

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.