What is it?

• A peptide produced by the human body
• A precursor to calcitonin and thus consistently produced by the thyroid gland C cells
• An acute phase reactant (and can be used as a marker of a bacterial infection in the body)

• procalcitonin levels parallel severity of the infection/systemic inflammation
• increases are detectable ~4 hours after exposure to endotoxin and peaks at 12-48 hours

Why isn’t procalcitonin produced in response to a
viral infection?

It is hypothesized that tumor necrosis factor (TNF) is essential to the synthesis of procalcitonin. When the body is exposed to a viral infection, the virus induces production of interferons which in turn suppresses TNF expression.

Why do we need it?

Studies have shown that up to 50% of antimicrobial use in the inpatient setting is unnecessary. Part of the reason is that we don’t always know who has a bacterial infection and who does not.

A blood test that can help differentiate types of infection and help shorten the duration of unnecessary antibiotics would be extremely helpful to physicians and beneficial to patients.

How does it work?

• Procalcitonin level is measured in the blood with a blood-draw
• Can be run from EDTA (purple) or heparin (green) tubes but NOT citrate-containing tubes
• Levels correlate with severity of the infection/systemic inflammation

When/how do you use it?

The data on how best to use procalcitonin and when to use it remains controversial, and each institution may have their own guidelines on how best to utilize it.

Studies demonstrate that procalcitonin can be used to determine:

• Whether to initiate antibiotic therapy
• Duration of antibiotic therapy
• Prognosis

The TWO scenarios with the most literature suggesting procalcitonin use is helpful are in guiding duration of antibiotic therapy in:

1. Lower Respiratory Tract Infections (LRTI)
2. Sepsis

Summary of some major trials in each area

1. Lower respiratory tract infections
   A) Schuetz et al. 2017 (Cochrane Systematic Review)
   – Cochrane systematic review of RCTs to evaluate procalcitonin in guiding initiation or discontinuation of antibiotics
   – moderate to high quality evidence; 6708 participants, 26 trials
   Primary outcomes: 1) all-cause mortality, 2) treatment failure at 30 days
   All-cause mortality:6% vs. 10% (controls); p-value = 0.037
   Treatment failure: no significant difference (23-24% in both groups)
   Secondary outcomes: 1) antibiotic use, 2) antibiotic-related side effects,
   3) Hospital Length of Stay (LoS)
   # of antibiotic days: 2.4 day reduction in antibiotic exposure (5.7 vs 8.1 days)
   Side effects of antibiotics: 16.3% vs. 22.1% (control), (p-value <0.001)
   LoS in hospital and ICU: no difference
   Summary: improved mortality and increase in antibiotic-free days between the two groups
   B) Huang et al. 2018 (ProACT study)
   – Multicenter RCT, 1656 patients enrolled
   – Procalcitonin was checked in the ED and followed during hospital course if patient was admitted
   – There was no difference in # of antibiotic exposure days over 30 days, rates of adverse events, or hospital length of stay (LoS)
   – There was no difference even when stratified by diagnosis of acute bronchitis, COPD, CAP, and other LRTI.
   Summary: no change in # of antibiotic-exposure days or adverse effects between the two groups
2. Severe sepsis/shock
   A) DeJong et al. 2016
   – Multicenter RCT in hospitals, 1575 enrolled
   Mortality: 20% vs. 25% (control) (p=0.0122)
   Median antibiotic duration: 7.5 days vs. 9.3 days (control); p-value <0.0001
   – There was a slightly higher risk of reinfection in the procalcitonin group (5% vs. 2.9%, p=0.0492)
   – No difference between ICU and hospital LoS between groups
   Summary: Use of procalcitonin reduced mortality and # of antibiotic exposure days but not LoS
   B) Andriolo et al. 2017 (Cochrane Systematic Review)
   – 10 trials, 1215 participants, low quality evidence
   – No significant differences in mortality at 28 days, ICU discharge, or hospital stay
   – Procalcitonin group had a mean 1.28 day less of antibiotic exposure than control group
   Summary: Use of pro-calcitonin reduced # antibiotic exposure days but not mortality
   C) Wirz et al. 2018
   – Meta-analysis of RCTs
   – 4482 patients overall
   Mortality: lower in the procalcitonin group (21.1% vs. 23.7%, p=0.03)
   # of antibiotic days: lower in procalcitonin group (9.3 vs. 10.4d, p<0.001)
   Summary: Use of procalcitonin reduces mortality and # of antibiotic exposure days

*It’s important to remember that all these trials have varying adherence to the protocols, various study populations, and centers with varying practice patterns that all affect the results of the studies.

**Procalcitonin should NOT typically be used for determine whether to initiate antibiotics in pneumonia or sepsis given the high risk of a poor outcome with a false negative result.

How to use it

1. Obtain procalcitonin at time of diagnosis and repeat every 1-2days.
2. Stop antibiotics when procalcitonin level is <0.1-0.5ng/ml or decreased by at least 50-90% from peak value

*Procalcitonin can also be used when it is unclear whether a patient has a bacterial infection or not to help guide further management.

Other potential uses of PCT

• Presence of bacterial infection in patients with COPD exacerbations, heart failure exacerbations, or bronchitis
• Aspiration pneumonia vs. pneumonitis
• Post-operative infections
• Fevers of unknown origin
• UTI therapy duration
• Bacterial vs. viral meningitis
• Febrile neutropenia
• Lower limb swelling
  (distinguishing between stasis dermatitis vs. thrombosis vs. cellulitis)
• Antibiotic stewardship
• And many others

Pharmacodynamics/kinetics

• short half-life (25-30 hours)
• dialyzed; in ESRD, levels tend to be higher prior to dialysis than after dialysis
  peak levels tend to correlate with severity of infection
• if inflammation is resolving, levels should decrease by ~50% every 1-2 days.
  ⇒mild elevation = 0.15-2ng/mL
  a) localized bacterial infection
  b) ESRD without recent hemodialysis
  c) noninfectious systemic inflammatory response
  ⇒significant elevation > 2ng/mL
  a) bacterial sepsis or severe localized bacterial infection
  b) severe non-infectious inflammatory stimuli (major burn, severe trauma, acute multisystem organ failure, bowel ischemia, stroke, major abdominal or cardiothoracic surgery)
  c) false positive from malignancy

False positives

• Malaria
• Candida spp.
• Pneumocystis jiroveci
• Pulmonary TB and some other non-tuberculosis mycobacterial infections
• Severe systemic stress (trauma, severe burns, surgery, cardiac arrest/shock, Addisonian crisis, pancreatitis, intracranial hemorrhage)
  *possibly due to gut translocation of LPS
• CKD/ESRD
• Patients receiving:
  1) T-cell antibody therapy
  2) ATG
  3) Alemtuzumab
  4) Rituximab
  5) IL-2 therapy
  6) Granulocyte transfusion
• Mushroom poisoning
• Immediate postnatal period
• Neuroendocrine tumors/medullary thyroid cancer/small cell lung cancer

False negatives

• atypical bacteria (i.e. Chlamydia and Mycoplasma pneumoniae, Legionella spp.)
• localized bacterial infections (tonsillitis, sinusitis, cystitis, uncomplicated SSTI, empyema/abscess, osteomyelitis)
• if drawn too early in infection (typically rises within 2-5 hours)

Practical advice

• Procalcitonin levels are NOT impaired in immunocompromised hosts (ICH)
  ⇒however, little information is known regarding use of procalcitonin in this patient population
  ⇒these patients have a low threshold for antibiotic initiation and prolonged duration thus no recommendations can be made to use procalcitonin to guide management in ICH at this time
  ⇒not enough data exists yet to support routine clinical use.
• Not enough data exists yet to support routine clinical use in surgical patients
  surgical patients may have a higher baseline procalcitonin level after certain surgeries
• Procalcitonin can be thought of similarly to B-natriuretic peptide (BNP) and as a more sensitive C-reactive protein (CRP). It can be used within a broader clinical context to support a diagnosis or decision regarding antibiotics and is useful in RULING OUT bacterial causes.

 

Take-home points:

• Use of procalcitonin and its algorithms should NOT override or replace clinical judgment.
• Serial measurements and trends are more helpful than one isolated value.
• A rising procalcitonin level is not, by itself, an indication to broaden antibiotic therapy.
• In order to use procalcitonin effectively, its essential to understand which pathogens induce elevations in procalcitonin.
• The use of procalcitonin has been most studied in LRTI and sepsis. The utility of procalcitonin in other situations remains unknown.
  

 

References:

1. Jin M and Khan A. Procalcitonin: Uses in the Clinical Laboratory for the Diagnosis of Sepsis. Laboratory Medicine. 2010; 41(3):173-177.
   https://doi.org/10.1309/LMQ2GRR4QLFKHCH9
2. Lin JLJ and Yap SL. Editor: Staros E. Medscape: Procalcitonin. Updated: Nov 24, 2015. https://emedicine.medscape.com/article/2096589-overview#a4
3. Rhee C and Mansour M. Procalcitonin use in lower respiratory tract infections. In: Ramirez JA, File TM, and Bond S. UpToDate. Waltham, Mass.: UpToDate, 2018. https://www.uptodate.com/contents/procalcitonin-use-in-lower-respiratory-tract-infections. Accessed September 8th, 2018.
4. Andriolo BN, Andriolo RB, Salomão R, and Atallah ÁN. Effectiveness and safety of procalcitonin evaluation for reducing mortality in adults with sepsis, severe sepsis or septic shock. Cochrane Database Syst Rev. 2017;1:CD010959.
5. Gilbert DN. Use of Plasma Procalcitonin levels as an adjunct to clinical microbiology. J Clin Microbiol. 2010; 48(7):2325-2329. doi: 10.1128/JCM.00655-10
6. de Jong E, van Oers JA, Beishuizen A, Vos P, Vermeijden WJ, Haas LE, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016; 16:819-827. doi: http://dx.doi.org/10.1016/S1473-3099(16)00053-0
7. Jensen JU, Heslet L, Jensen TH, Espersen K, Steffensen P, and Tvede M. Procalcitonin increase in early identification of critically ill patients at high risk of mortality. Crit Care Med. 2006; 34:2596-2602.
8. Riedel S, Melendez JH, An AT, Rosenbaum JE, and Zenilman JM. Procalcitonin as a marker for the detection of bacteremia and sepsis in the emergency department. Am J Clin Pathol. 2011; 135(2):182-189. doi: 10.1309/AJCP1MFYINQLECV2.
9. Kollef MH. Clinical presentation and diagnostic evaluation of ventilator-associated pneumonia. In: Manaker S and Finlay G, ed. UpToDate. Waltham, Mass.: UpToDate, 2018. https://www.uptodate.com/contents/clinical-presentation-and-diagnostic-evaluation-of-ventilator-associated-pneumonia. Accessed September 10, 2018.
10. Schuetz P, Wirz Y, Sager R, Christ-Crain M, Stolz D, Tamm M, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2017; 10:CD007498. doi: 10.1002/14651858.CD007498.pub3
11. Huang DT, Yealy DM, Filbin MR, Brown AM, Chang CCH, Doi Y, et al. Procalcitonin-Guided Use of Antibiotics for Lower Respiratory Tract Infection. NEJM. 2018; 379:236-49. doi: 10.1056/NEJMoa1802670.
12. Wirz Y, Meier MA, Bouadma L, Luyt CE, Wolff M, Chastre J, et al. Effect of procalcitonin-guided antibiotic treatment on clinical outcomes in intensive care unit patients with infection and sepsis patients: a patient-level meta-analysis of randomized trials. Critical Care. 2018; 22:191. https://doi.org/10.1186/s13054-018-2125-7.