Procalcitonin

Reviewed and revised 20 December 2015

OVERVIEW

  • Procalcitonin is the propeptide of calcitonin, a 116-peptide molecule with a molecular weight of 13 kDa
  • Procalcitonin has been studied as a sepsis biomarker, to help with diagnosing/ ruling out sepsis and to guide the initiation and cessation of antibiotics

PATHOPHYSIOLOGY

Production

  • produced by the C-cells of the thyroid gland and released in low concentrations in health (plasma concentration <0.1 ng/mL)
  • in sepsis is has extrathyroidal origin from inflamed/infected tissue, mostly neuroendocrine cells in the lungs and intestine
  • synthesis is triggered by bacterial endotoxin and inflammatory cytokines
  • levels rise significantly during severe infection or inflammation (particularly in bacterial origin)

Kinetics

  • lag time of 2 to 4 h after the onset of sepsis
  • peaks at 24-48 h of sepsis
  • Cleared by the parathyroid gland; renal clearance is low
  • Correlates with extent and severity of bacterial infection
  • Circulating procalcitonin levels halve daily when the infection is controlled by the host immune system or antibiotic therapy (less rapid fall in severe renal dysfunction)

Biological functions of procalcitonin

  • modulation of immunologic functions and vasomotility
  • has time-dependent effects
    • augments migratory response of monocytic cells initially, but causes inhibition after a period of hours of incubation with PCT
    • inhibits expression of inducible nitric oxide synthase (iNOS) in vascular smooth muscle cells, but augments it in prestimulated cells
  • alters expression of cytokines
  • likely has different effects in patients with severe sepsis/ septic shock versus non-septic patients

ADVANTAGES

Uses

  • potentially useful in identifying occult bacterial infection
  • potentially useful for ruling out serious bacterial infection
  • Useful in discriminating between bacterial and non-infectious causes of inflammation, as its synthesis is triggered by bacterial endotoxin
  • can help guide duration of antibiotic therapy
  • can help with decision to initiate antibiotic therapy in non-ICU patients
  • predicts fatal outcome in CAP and critically ill septic patients (high levels correlate with organ dysfunction; persistently high levels associated with higher mortality)

Other

  • strongly correlates with extent and severity of bacterial infections, better indicator of illness severity than CRP
  • Numerous trials (related to industry support) providing evidence for assisting decision making in RTIs, pyelonephritis, bacteremia and post-operative infections
  • levels peak rapidly after the first appearance of endotoxin, i.e. before blood cultures have time to incubate
  • better at differentiating SIRS from sepsis compared to CRP and other biomarkers (e.g. IL-2, 6, 8 and TNF-alpha)
  • not too expensive
  • can provide a quick result (in around 30 min), whereas blood cultures can take 24 hours
  • not elevated in viral infection or autoimmune disorders
  • procalcitonin production is not decreased by steroids (up to 30mg prednisolone)
  • compared to CRP: more rapid rise and fall, more specific and sensitive for bacterial sepsis, better correlation with severity

DISADVANTAGES

  • more expensive and less available than other commonly used biomarkers (e.g. CRP)
  • can increase in non-septic SIRS conditions characterised by massive cell death (e.g. after trauma or surgery)
  • not useful for identifying local infection/collections without a systemic response (may be normal in endocarditis)
  • not useful for identifying  viral infection or fungal infection
  • does not identify source of infection
  • may not elevate in the immunocompromised
  • uncertain role in pancreatitis and intra-abdominal infections
  • different studies used different cut-offs (disagreement as to appropriate negative cut-off point)
  • uncertain cost-effectiveness
  • Requires serial measurements (more expense)
  • 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 include:
    • Burns
    • Massive tissue necrosis
    • Rhabdomyolysis
    • Tumour lysis
    • Cardiac or major abdominal surgery
    • Multi-organ system failure
    • Cardiogenic shock
    • Severe liver and renal dysfunction
    • Treatment with T-cell antibodies
    • Paraneoplastic production, eg. by medullary thyroid carcinoma or by small-cell lung cancer

EVIDENCE

  • Meta-analysis data is conflicting; some studies suggest procalcitonin is superior to CRP while other have concluded it is a weak biomarker in critical illness
  • A few prospective RCTs (e.g. PRORATA and studies of outpatient management of respiratory tract infections) have shown a decrease in prescription and cost of antibiotic therapy with no change in outcome. This benefit will vary with different settings, depending on antibiotic stewardship programs and clinican willingness to stop antibiotics in patients who are clinically improving

PRORATA Study, 2010:

  • MC-RCT of 8 ICUs, n = 621 patients
  • procalcitonin used to determine cessation of antibiotics therapy
  • Outcomes:
    — no significant difference in outcomes (mortality at 28 days)
    — BUT significant reduction in antibiotic use: 6.1 vs. 9.9 days (P<0.0001)
  • Commentary and criticisms:
    — only 10% were surgical ICU patients
    — 53% of patients randomized to procalcitonin arm did not follow the algorithm-guided treatment
    — The analysis used a 10% margin of non-inferiority threshold for mortality. If a 5% margin of non-inferiority for mortality had been used instead, the procalcitonin arm would have had inferior mortality at 60 days
    — cost-effectiveness not assessed

Hoeboer et al, 2015; systematic review and meta-analysis:

  • 58 of 1567 eligible studies were included providing a total of 16 514 patients; of whom 3420 had bacteraemia
  • area under the SROC curve was 0.79
  • optimal and most widely used procalcitonin cut-off value was 0.5 ng/mL
  • overall sensitivity of 76% and specificity of 69%
  • least useful in immunocompromised/neutropenic patients (ROC AUC = 0.71) and best in ICU patients; with sensitivities ranging from 66 to 89% and specificities from 55 to 78%
  • Conclusions: low procalcitonin levels can be used to rule out the presence of bacteraemia; further research is needed on the safety and efficacy of procalcitonin as a single diagnostic tool to avoid taking blood cultures

Other studies in progress include:

  • Stop Antibiotics on guidance of Procalcitonin Study (SAPS)
  • PASS study

AN APPROACH

  • Procalcitonin is not routinely used at my institution, where we primarily rely upon careful clinical assessment in conjunction with microbiological testing and a well developed antibiotic stewardship programme

Suggested approach if procalcitonin is used (based on Meissner, 2014):

  • threshold to exclude sepsis: plasma concentration of ≤0.2 ng/mL (high negative predictive value)
  • threshold to diagnose sepsis: plasma concentration of ≥0.5 ng/mL
  • check procalcitonin daily in patients with suspected sepsis
  • patients with a strong clinical suspicion of sepsis should still be treated as such even if procalcitonin is not initially elevated; serial levels and clinical assessment should be performed over the next few days to determine if antibiotics should be ongoing
  • as a rule of thumb, a daily drop of >30% in procalcitonin level suggests resolving inflammation
    • consider changing antibiotics if the procalcitonin level is≥0.5 ng/mL and not falling
    • consider continuing antibiotics if the procalcitonin level is ≥0.5 ng/mL or has fallen by <80% from peak level
    • consider stopping antibiotics if the procalcitonin level is ≤0.5 ng/mL or has fallen by >80% from peak level
  • do not use procalcitonin to guide antibiotic therapy in severe local infections that require antibiotics (e.g. endocarditis, osteomyelitis) or patients unlikely to mount a procalcitonin response (e.g. neutropenia, immunosuppression)
  • use procalcitonin as part of an antibiotic stewardship programme

References and Links

LITFL

Journal articles

  • Bouadma L, et al; PRORATA trial group. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet. 2010 Feb 6;375(9713):463-74. PMID: 20097417.
  • Foushee JA, Hope NH, Grace EE. Applying biomarkers to clinical practice: a guide for utilizing procalcitonin assays. The Journal of antimicrobial chemotherapy. 67(11):2560-9. 2012. [pubmed] [free full text]
  • Kibe S, Adams K, Barlow G. Diagnostic and prognostic biomarkers of sepsis in critical care. J Antimicrob Chemother. 2011 Apr;66 Suppl 2:ii33-40. doi: 10.1093/jac/dkq523. PMID: 21398306.
  • Meisner M. Update on procalcitonin measurements. Annals of laboratory medicine. 34(4):263-73. 2014. [pubmed]
  • Póvoa P, Salluh JI. Biomarker-guided antibiotic therapy in adult critically ill patients: a critical review. Ann Intensive Care. 2012 Jul 23;2(1):32. PMC3475044.
  • Schuetz P, Albrich W, Mueller B. Procalcitonin for diagnosis of infection and guide to antibiotic decisions: past, present and future. BMC Med. 2011 Sep 22;9:107. PMC3186747.
  • Shehabi Y, Seppelt I. Pro/Con debate: is procalcitonin useful for guiding antibiotic decision making in critically ill patients? Crit Care. 2008;12(3):211. PMC2481434.
  • Wacker C, Prkno A, Brunkhorst FM, Schlattmann P. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis. 2013 Jan 31. PMID: 23375419.

CCC 700 6

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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