Procalcitonin

Article Author:
Derrick Cleland
Article Editor:
Ambika Eranki
Updated:
9/16/2019 8:55:41 PM
PubMed Link:
Procalcitonin

Introduction

In today’s clinical practice, procalcitonin (PCT) has developed into a promising new biomarker for early detection of (systemic) bacterial infections. PCT is a 116-amino acid residue that was first explained by Le Moullec et al. in 1984; however, its diagnostic significance was not recognized until 1993. In 1993, Assicot et al. demonstrated a positive correlation between high serum levels of PCT and patients with positive findings for bacterial infection and sepsis (eg, positive blood cultures). Further, they demonstrated that PCT did not elevate in viral infections and that serum levels of PCT would decrease following administration of appropriate antibiotic therapies. Current inflammatory biomarkers, such as C-reactive protein (CRP), lack the specificity required to diagnose bacterial versus non-bacterial infections accurately. Therefore, PCT assays with a specificity of 79%, have since been developed and utilized to more accurately determine if a bacterial species is the cause of a patient’s systemic inflammatory reaction.[1][2][3][4]

Pathophysiology

Under normal homeostasis, pre-procalcitonin undergoes initial synthesis by thyroid C cells. Later this peptide is transformed into procalcitonin via cleavage of a 25-amino acid signal sequence by endopeptidases. The end product calcitonin, the 32-amino acid hormone responsible for serum calcium regulation, is then formed following conversion by the enzyme prohormone convertase. Normally, physiological conditions result in very low serum procalcitonin levels (less than 0.05 ng/mL). However, the synthesis of PCT can be increased (up to 100 to 1000 fold) as a result of endotoxins and/or cytokines (eg, interleukin (IL)- 6, tumor necrosis factor (TNF)-alpha, and IL-1b), which act on various tissues. The extra-thyroid synthesis of PCT has been found to occur in the liver, pancreas, kidney, lung, intestine and within leukocytes; however, it merits noting that the synthesis of PCT has been shown to be suppressed within these tissues in the absence of bacterial infection. In contrast, cytokines, such as interferon (INF)-gamma, which get released following viral infection, lead to down-regulation of PCT, thus highlighting another advantage of PCT assays.[5][6][7]

Diagnostic Tests

KINETICS

Procalcitonin serum levels have been shown to increase 6 to 12 hours following initial bacterial infections and increase steadily 2 to 4 hours following the onset of sepsis. The half-life of PCT is between 20 to 24 hours; therefore, when a proper host immune response and antibiotic therapy are in place, PCT levels decrease accordingly by 50% over 24 hours.[8][5][6]

CHEMICAL ASSAYS

In current clinical practice, several chemical assays have been developed to detect procalcitonin serum levels at varying sensitivities, most displaying functional sensitivity around 0.06 ng/mL. One of the first commercially available assays was a homogenous immunoassay that utilizes time-resolved amplified cryptate emission technology. The assay is composed of sheep polyclonal anti-CT antibody and a monoclonal anti-katacalcin antibody which binds to the CT and katacalcin amino acid sequence of PCT via the sandwich method. The assay takes 19 min to complete, and results are typically obtained within 1 hour following serum draw, using 20 to 50 microliters of plasma or serum.[2][7][9]

Interfering Factors

Although procalcitonin assays have shown promising results over the years, there are still several limitations that require consideration before implementing these tests in everyday clinical practice. For instance, it has been shown that PCT serum levels can also become elevated among patients during times of noninfectious conditions, such as with trauma, burns, carcinomas (medullary C-cell, small cell lung, & bronchial carcinoid), immunomodulator therapy that increase proinflammatory cytokines, cardiogenic shock, first 2 days of a neonate's life, during peritoneal dialysis treatment, and in cirrhotic patients (Child-Pugh Class C). Furthermore, PCT levels have found to be falsely elevated in patients suffering from various degrees of chronic kidney disease which can, in turn, alter baseline results making the determination of an underlying bacterial infection difficult to establish. Thus, it is vital for the clinician to rule out the above scenarios to ensure there are no confounding issues that may be obscuring the PCT measurements.[4][10][4]

The cost-effectiveness of PCT assays needs to be considered as well because they currently suffer from overuse in the emergency setting leading to extraneous costs. The average price of the test is roughly $9.44, which is relatively inexpensive. However, this cost does not take into account the amount that insurance charges nor does it include the cost it requires to obtain the sample. Salinas et al. discovered that of 142644 PCT assays performed in a calendar year, 44.1% could have been avoided based on clinical presentation and outcome, which would have saved $594390 annually. Within the Intensive Care setting, Kip et al. performed a randomized control trial to determine the cost-effectiveness of PCT assays among septic patients. They determined that PCT assays improved mortality rates and decreased the clinical course of antibiotics, however, they found that the cost per patient was $2704 (on average) greater than the patients who did not receive the PCT assays during their hospital stay. Therefore, clinicians need to use precaution when ordering PCT assays to ensure cost-effective medical practice.[11][12]

Results, Reporting, Critical Findings

Procalcitonin has a set half-life that provides clinicians and researchers with a rough timeline of when levels should begin to decrease (approximately 50% reduction over 24 hours) following physiological control of the systemic infection. Current clinical practice utilizes a variety of PCT cut-off levels to determine the initiation and discontinuation of antibiotic therapy. The clinical scenario and setting play a fundamental role as to which cut-off level should be employed. However, most research has shown that PCT levels display clinical significance when they are in the range of 0.1 to 0.5 ng/mL. Further, research has shown that PCT levels less than 0.1 ng/mL have been shown to have a high negative predictive value (96.3%) for excluding bacterial infections.[5][6][2]

The following clinical scenarios have utilized various PCT cut-off levels to determine the source of an infective process as well as when antibiotic therapy could be utilized/discontinued[6]:

Arthritis: 

  • PCT cut-off level: 0.1 to 0.25 ng/mL
  • Role of PCT: Discriminate infective (septic) arthritis from non-infective arthritis.  
  • Type of Study: Observational

Bacteremic Infections

  • PCT cut-off level: 0.25 ng/mL
  • Role of PCT: To rule out bacteremic infections. 
  • Type of Study: Observational

Blood Stream Infection (primary): 

  • PCT cut-off level: 0.1 ng/mL
  • Role of PCT: Differentiate between true infection and a contaminated sample. 
  • Type of Study: Observational

Bronchitis (acute)/Chronic Obstructive Pulmonary Disease (COPD) Exacerbations: 

  • PCT cut-off level: 0.1 to 0.5 ng/mL
  • Role of PCT: Reduce (unnecessary) antibiotic exposure in the ED and inpatient setting without adverse outcomes. 
  • Type of Study: Randomized Control Trial  

Endocarditis: 

  • PCT cut-off level: 2.3 ng/mL
  • Role of PCT: High diagnostic accuracy for predicting acute endocarditis. 
  • Type of Study: Observational

Meningitis: 

  • PCT cut-off level: 0.5 ng/mL
  • Role of PCT: Differentiate viral from bacterial meningitis and subsequently reduced antibiotic exposure.
  • Type of Study: Before-After

Neutropenia

  • PCT cut-off level: 0.1 to 0.5 ng/mL
  • Role of PCT: Identify systemic bacterial infections within neutropenic patients. 
  • Type of Study: Observational

Pneumonia

  • PCT cut-off level: 0.1 to 0.5 ng/mL
  • Role of PCT: Reduce antibiotic exposure during hospitalization without adverse outcomes.

Postoperative Fever

  • PCT cut-off level:0.1 to 0.5 ng/mL
  • Role of PCT: Differentiate post-operative infections from non-infectious fever. 
  • Type of Study: Observational

Postoperative Infections: 

  • PCT cut-off level: 0.5 to 1.0 ng/mL
  • Role of PCT: Minimize antibiotic treatment in surgical ICU without detrimental outcomes. 
  • Type of Study: Randomized Control Trial

Severe Sepsis/Shock

  • PCT cut-off level: 0.25 to 0.5 ng/mL
  • Role of PCT: Limit antibiotic treatment in the ICU without detrimental outcomes.
  • Type of Study: Randomized Control Trial

Upper Respiratory Tract Infections

  • PCT cut-off level: 0.1 to 0.25 ng/mL
  • Role of PCT: Limit antibiotic treatment in the ICU without detrimental outcomes.
  • Type of Study: Randomized Control Trial

Urinary Tract Infections: 

  • PCT cut-off level: 0.25 ng/mL
  • Role of PCT: Determine the extent of renal involvement. 
  • Type of Study: Observational

Ventilator-Associated Pneumonia[6]

  • PCT cut-off level: 0.1 to 0.25 ng/mL
  • Role of PCT: Minimize antibiotic treatment without detrimental outcomes. 
  • Type of Study: Randomized Control Trial

Once the clinician establishes the cut-off level, it is then important to determine how often PCT measurements should be repeated to determine adequate control. Current clinical data suggests that PCT serum levels should be remeasured after 6 to 24 hours, absent evidence of spontaneous clinical improvement (eg, hemodynamic instability). Following antibiotic initiation, the recommendation is that PCT values be assessed every one to two days to ensure adequate coverage. Further, antibiotic courses should be discontinued as soon as PCT levels drop below 0.1 ng/mL or 80 to 90% below the initial measurement.[6]

Algorithms have since been established for the ED and ICU setting which provide clinicians with a quick method for determining when to initiate or discontinue antibiotics. In the ED, an algorithm has been established for determining when to start antibiotic therapy in patients with respiratory tract infections. Recommendations are that antibiotics be utilized when PCT levels are above 0.25 ng/mL and that PCT levels be repeated on days 3,5, and 7 and to stop antibiotics if they fall below 0.25 ng/mL or drop by 80 to 90%. If PCT remains elevated then consider new treatment options. In the ICU, an algorithm has been instituted to determine when antibiotic treatment should be discontinued in patients with sepsis. The algorithm recommends that antibiotic coverage should be discontinued when PCT levels drop below 0.5 ng/mL or a decrease of 80% from the peak value. However, if PCT levels continue to remain elevated (over 0.5 ng/mL), then it is advised to continue the antibiotic course or consider changing the treatment entirely. These algorithms have been used with great success in clinical trials and have proven to reduce overall antibiotic use thus improving antibiotic stewardship. However, further research is needed to ensure these results can be adequately repeated on a larger scale and by utilizing more clinical trials versus observational studies.[6]

Clinical Significance

It is well-documented that early diagnosis of a bacterial infection can lead to a decrease in mortality and morbidity among all patients. Efficient diagnosis of bacterial infections allows physicians to initiate antibiotic therapy when it is deemed appropriate, thus preventing the misuse and overuse of antibiotics. As antibiotic resistance continues to rise, it has become ever more important for clinicians to determine different algorithms and laboratory tests that help sustain current antibiotic parameters. Unfortunately, most of the first-line tests for determining infection, such as blood cultures and C-reactive protein (CRP), lack the efficiency and specificity needed to treat patients promptly. Therefore, procalcitonin serum assays have been developed to provide physicians and nurses with an earlier detection method for determining the origin of a systemic inflammatory response (eg, bacterial versus non-bacterial). Early detection, in turn, limits the development of antibacterial resistance as well as patient exposure to antibiotics when they are no longer warranted. 

The prognostic value of procalcitonin has also shown clinical significance by providing physicians with a positive correlation between disease severity and elevated PCT serum levels, especially within septic patients. Although PCT assays have shown great promise, the cost-effectiveness of these tests continues to be a topic of debate. Current research has shown that these tests are already being overused because there are currently no adequate guidelines in place for when these tests should and should not be obtained. Therefore, the clinical significance of these tests needs to be more thoroughly researched on a large scale and by way of randomized clinical trials (gold standard) so that guidelines can be implemented to ensure the practice of cost-effective medicine.[5][6][7][11][12]

Enhancing Healthcare Team Outcomes

As bacterial drug resistance continues to rise across the globe, it has become of utmost importance to enhance antibiotic stewardship. Procalcitonin (PCT) provides healthcare providers with a more specific marker (specificity of ~79%) for determining the presence of bacterial infections when compared to current measures. Therefore, PCT assays can be utilized to determine if antibiotics need to be initiated, discontinued, or changed based on changing serum levels thus decreasing the overall use or misuse of antibiotics. Moreover, the assays have also been shown to be useful as a prognostic indicator for patients in the critical care setting, however, further research needs to be performed in this respect to determine if PCT assays are adequate for this purpose. [4][6]

Procalcitonin has utility in a number of clinical scenarios, however, current research suggests that PCT levels are most useful in the setting of acute exacerbations of Chronic Obstructive Pulmonary Disease (COPD) patients to determine when and if antibiotics should be initiated. The European Respiratory Society/American Thoracic Society guidelines currently state that the use of antibiotics in the setting of COPD exacerbations is controversial because there is inadequate research showing improvement in clinical outcomes following the use of antibiotics. Therefore, they recommend further effectiveness studies and/or the use of biomarkers to determine when antibiotics are clinically appropriate. A biomarker, such as procalcitonin, can thus be utilized to determine if antibiotics are appropriate in the setting of acute COPD exacerbations, which in turn, improves antibiotic stewardship and reduces morbidity associated with unnecessary antibiotic use. [6][13]

Overall, procalcitonin levels provide a promising lab value for identifying bacterial infections, however, this test is limited based on the clinical setting and patient population for which it is utilized. Therefore, further research studies (eg, Randomized Clinical Trials) need to be conducted prior to implementing procalcitonin guidelines for everyday clinical practice. 


References

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[2] Riedel S,Melendez JH,An AT,Rosenbaum JE,Zenilman JM, Procalcitonin as a marker for the detection of bacteremia and sepsis in the emergency department. American journal of clinical pathology. 2011 Feb;     [PubMed PMID: 21228358]
[3] Assicot M,Gendrel D,Carsin H,Raymond J,Guilbaud J,Bohuon C, High serum procalcitonin concentrations in patients with sepsis and infection. Lancet (London, England). 1993 Feb 27;     [PubMed PMID: 8094770]
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[6] Procalcitonin for diagnosis of infection and guide to antibiotic decisions: past, present and future., Schuetz P,Albrich W,Mueller B,, BMC medicine, 2011 Sep 22     [PubMed PMID: 21936959]
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[8] Becker KL,Nylén ES,White JC,Müller B,Snider RH Jr, Clinical review 167: Procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors. The Journal of clinical endocrinology and metabolism. 2004 Apr;     [PubMed PMID: 15070906]
[9] Meisner M, Pathobiochemistry and clinical use of procalcitonin. Clinica chimica acta; international journal of clinical chemistry. 2002 Sep;     [PubMed PMID: 12135804]
[10] Grace E,Turner RM, Use of procalcitonin in patients with various degrees of chronic kidney disease including renal replacement therapy. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2014 Dec 15;     [PubMed PMID: 25228701]
[11] Salinas M,López-Garrigós M,Flores E,Uris J,Leiva-Salinas C, Procalcitonin in the Emergency Department: A potential expensive over-request that can be modulated through institutional protocols. The American journal of emergency medicine. 2018 Jan;     [PubMed PMID: 28768585]
[12] Kip MMA,van Oers JA,Shajiei A,Beishuizen A,Berghuis AMS,Girbes AR,de Jong E,de Lange DW,Nijsten MWN,IJzerman MJ,Koffijberg H,Kusters R, Cost-effectiveness of procalcitonin testing to guide antibiotic treatment duration in critically ill patients: results from a randomised controlled multicentre trial in the Netherlands. Critical care (London, England). 2018 Nov 13;     [PubMed PMID: 30424796]
[13] Wedzicha JA Ers Co-Chair,Miravitlles M,Hurst JR,Calverley PM,Albert RK,Anzueto A,Criner GJ,Papi A,Rabe KF,Rigau D,Sliwinski P,Tonia T,Vestbo J,Wilson KC,Krishnan JA Ats Co-Chair, Management of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. The European respiratory journal. 2017 Mar     [PubMed PMID: 28298398]