Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Procalcitonin (ProCT) is a 116 amino acid precursor of calcitonin (CT). ProCT is processed to an N-terminal 57 amino acid peptide. CT (32 amino acid) and a 21 amino acid C-terminal peptide, catacalcin (CCP-1). Expression of this group of peptides is normally limited to thyroid C-cells and, to a small extent, other neuroendocrine cells. CT is the only hormonally active of these peptides. CT is secreted by C-cells in response to hypercalcemia and inhibits bone resorption by osteoclasts, minimizing oscillations in serum calcium and calcium loss.
During severe systemic inflammation, in particular related to bacterial infection, the tissue specific control of CT-related peptides expression breaks down and ProCT and CCP-1 (referred collectively to as ProCT) are secreted in large quantities by many tissues. CT levels do not change. ProCT may contribute to sepsis-related death. Decreased mortality after treatment with anti-ProCT antibodies has been demonstrated in animal models of sepsis.
Noninfectious inflammatory stimuli need to be extremely severe to result in ProCT elevations, making it a more specific marker for severe infections than most other inflammatory markers (cytokines, interleukins, and acute-phase reactants). ProCT elevations are also more sustained than those of most other markers and occur in neutropenic patients. This reduces the risk of false-negative results.
ProCT becomes detectable within 2 to 4 hours after a triggering event and peaks by 12 to 24 hours. ProCT secretion parallels closely the severity of the inflammatory insult, with higher levels associated with more severe disease and declining levels with resolution of illness. In the absence of an ongoing stimulus, ProCT is eliminated with a half-life of 24 to 35 hours, making it suitable for serial monitoring. Finally, the dependence of sustained ProCT elevations on ongoing inflammatory stimuli allows identification of secondary septic events in conditions that can result in noninfectious ProCT elevations, such as cardiac surgery, severe trauma, severe burns, and multiorgan failure. ProCT levels should fall at a predictable pace in the absence of secondary infection.
Diagnosis of bacteremia and septicemia in adults and children (including neonates)
Diagnosis of renal involvement in urinary tract infection in children
Diagnosis of bacterial infection in neutropenic patients
Diagnosis, risk stratification, and monitoring of septic shock
Diagnosis of systemic secondary infection post-surgery, and in severe trauma, burns, and multiorgan failure
Differential diagnosis of bacterial versus viral meningitis
Differential diagnosis of community-acquired bacterial versus viral pneumonia
Monitoring of therapeutic response to antibacterial therapy
-In children older than 72 hours and in adults, levels <0.15 ng/mL make a diagnosis of significant bacterial infection unlikely.
-Mild elevations between 0.15 a ng/mL and 2.0 ng/mL are consistent with localized mild-to-moderate bacterial infection, but can also be seen in patients with noninfectious systemic inflammatory response.
-Levels >2.0 ng/mL are highly suggestive of systemic bacterial infection/sepsis or severe localized bacterial infection, such as severe pneumonia, meningitis, or peritonitis. They can also occur after severe noninfectious inflammatory stimuli such as major burns, severe trauma, acute multiorgan failure, or major abdominal or cardiothoracic surgery. In cases of noninfectious elevations, procalcitonin (ProCT) levels should begin to fall after 24 to 48 hours.
-Autoimmune diseases, chronic inflammatory processes, viral infections, and mild localized bacterial infections rarely lead to elevations of ProCT of >0.5 ng/mL.
Specific diagnostic applications, based on the current consensus in the literature:
-Diagnosis of bacteremia and septicemia in adults and children (including neonates):
- In children <72 hours old, whether born term or preterm, higher cutoff levels may be appropriate. There is no consensus in the literature, but the most recent publications suggest diagnostic cutoffs for the diagnosis of serious bacterial infection of >1.0 ng/mL at birth, > or =100 ng/mL at 24 hours, and > or =50 ng/mL at 48 hours of age. Adult levels should apply at > or = 72 hours.
-Diagnosis of renal involvement in pediatric urinary tract infections:
- In children with urinary tract infections, a ProCT level of >0.5 ng/mL has a 70% to 90% sensitivity and an 80% to 90% specificity for renal involvement.
-ProCT responses in neutropenic patients are similar to patients with normal neutrophil counts and function, and the cutoffs discussed under general considerations above should be used.
In the appropriate clinical setting, a ProCT of >2.0 ng/mL predicts sepsis and a level of >10 ng/mL indicates likely septic shock. Reported sensitivity and specificity for the diagnosis of sepsis range from 60% to 100%, depending on underlying and coexisting diseases and the patient populations studied. The higher the ProCT level the worse the prognosis. ProCT concentrations of >20 ng/mL are associated with a guarded prognosis. However, universally accepted risk-scoring systems for ProCT levels in sepsis have not been developed. When sepsis has been successfully treated, ProCT levels should fall with a half-life of 24 to 35 hours.
ProCT levels that are elevated in noninfectious, severe inflammatory conditions should start falling within 48 hours of the initial toxic stimulus with a half-life of 24 to 35 hours. Persistent high levels or secondary peaks suggest secondary infection.
A ProCT level of <0.5 ng/mL makes bacterial meningitis very unlikely. Most patients with bacterial meningitis will have ProCT levels of >10 times this level.
With successful antibiotic therapy, ProCT levels should fall with a half-life to 24 to 35 hours.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Severe trauma, major burns, multiorgan failure, or major surgery can cause procalcitonin (ProCT) elevations in the absence of sepsis. After removal of the noxious stimulus, ProCT should start to fall.
Patients with untreated end-stage renal failure may have ProCT levels of >0.15 ng/mL in the absence of infection or severe inflammation. Within 3 hemodialysis treatments this should fall to the normal reference range. End-stage renal failure patients on stable hemodialysis or peritoneal dialysis treatments have ProCT levels similar to healthy adults with normal renal function.
Patients with medullary thyroid carcinoma or, very rarely, islet cell tumors may have significant elevations in ProCT in the absence of sepsis. In certain cases, these levels may exceed 10,000 ng/mL.
Some infants and children may have ProCT levels from 0.15 ng/mL to 0.50 ng/mL for unknown reasons.
As with all immunometric assays, there is a low but definite possibility of false-positive results in patients with heterophile antibodies. Test results that do not fit the clinical picture should therefore be discussed with the laboratory.
A hook effect can occur at ProCT concentrations >2,500 ng/mL (extremely rare), resulting in a lower measured ProCT concentration than is actually contained in the specimen. This may complicate the interpretation of serial ProCT measurements in rare patients with extremely high ProCT levels. If there is clinical suspicion of this occurring, then retesting after specimen dilution should be requested.
Note: A "high-dose hook" effect was observed at Mayo Clinic in a patient specimen with a ProCT concentration of 10,270 ng/mL (calcitonin 313,600 pg/mL). This specimen appeared to have a ProCT value of only 2.8 ng/mL when measured without dilution.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
Children >72 hours-adults: < or =0.15 ng/mL
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Meisner M: Pathobiochemistry and clinical use of procalcitonin. Clin Chim Acta 2002;323:17-29
2. Sitter T, Schmidt M, Schneider S, Schiffle H: Differential diagnosis of bacterial infection and inflammatory response in kidney disease using procalcitonin. J Nephrol 2002;15:297-301
3. Becker KL, Nylen ES, White JC, et al: Procalcitonin and the calcitonin family of peptides in inflammation, infection and sepsis: a journey from calcitonin back to its precursors. J Clin Endocrinol Metab 2004;89:1512-1525
4. Van Rossum AM, Wulkan RW, Oudesluys-Murphy AM: Procalcitonin as an early marker of infection in neonates and children. Lancet Infect Dis 2004;4:620-623
5. Uzzan B, Cohen R, Nicolas P, et al: Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis. Crit Care Med 2006;34(7):1996-2003