Question 23

College Answer

Diagnosis

•    PCT   is   synthesized   physiologically   by   thyroid   C   cells   but   in   sepsis   has extrathyroidal origin from the inflamed/infected tissue
•    The biochemical and clinical profile well described
•    It is easy to perform (Blood test), not too expensive and provides a quick answer in about 30 minutes. Blood cultures can take up to 24 hours.
•    PCT is no gold standard for infection. There number of reports of PCT elevation in non-septic SIRS, immediately after surgery and trauma.
•    Data from meta-analyisis  are conflicting,  some suggesting  it is superior to CRP, whilst others have concluded it is a weak biomarker in critical illness.
•    PCT    is    not    elevated    in    viral    infection,    autoimmune     disorders     and immunocompromised   patients  –  hence  empiric  therapy  still  the  way  in  these patients.
•    PCT does not tell you the site of infection/inflammation. History, clinical examination and other investigations like CT scan can.
•    PCT  is a biomarker  and  cannot  replace  good  history  taking,  systematic  clinical examination, appropriate investigations for the source of sepsis.

Management

Few prospective randomised studies using,PCT   as a guide to antibiotic therapy, have showed that prescription  rate and the cost of antibiotics  was reduced significantly  with similar outcomes compared to the conventional approach
(Mention  of the recent  Lancet  paper  (Jan2010  – ProRata  study and its conclusions  is worthy of extra credit).

Discussion

If one were to approach this in a structured fashion, the answer would resemble the following:

• 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 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)
    • SAPS study (2013)
  • Overall, according to a recent meta-analysis (2015)
  • • "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
• 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.