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 (i.e., 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.
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 (i.e., 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.
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.
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 which utilizes time-resolved amplified cryptate emission technology. The assay is composed of sheep polyclonal anti-CT antibody and a monoclonal anti-katacalcin antibody which bind 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.
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.
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:
Blood Stream Infection (primary):
Bronchitis (acute)/Chronic Obstructive Pulmonary Disease (COPD) Exacerbations:
Upper Respiratory Tract Infections
Urinary Tract Infections:
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 (i.e., 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.
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.
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). 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.
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.
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 (i.e., 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 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.
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