PROCALCITONIN AS AN INFECTION MARKER
PCT - MOLECULE
Procalcitonin (PCT) is a 116 amino acid protein with a sequence identical to that of the prohormone of calcitonin (32 amino acids).
Under normal metabolic conditions, hormonally active calcitonin is produced and secreted in the C-cells of the thyroid gland after specific intracellular proteolytic procession of the prohormone PCT. Thus, under normal conditions the PCT levels in the circulation are very low (< 0.05 ng/ml). The PCT molecule is very stable both in vivo and in vitro. The in vivo half-life time of PCT is about 24 hours.
PCT - KINETICS
Even though this molecule was firstly used as a tumoral marker, nowadays the main interest of this molecule is focalized on his role as an infection marker. Infact high levels of procalcitonin are seen in bacterial infection despite the low levels(< 2 ng/ml) founded in viral infections, chronic inflammatory disorders or autoimmune processes. Remarkably the high procalcitonin levels produced during infections are not followed by a parallel increase in calcitonin or calcium serum levels.
That is because bacterial infections induce an ubiquitous increase of CALC-1 gene expression and a constitutive release of PCT from all parenchymal tissues and differentiated cell types throughout the body, so that significant concentrations of PCT (up to 1000 ng/ml) can be detected in the blood of patients with severe bacterial infection/sepsis.
Quantitative Analysis of CT-mRNA Expression by Taq-Man PCR technology shows a significant induction in all septic tissues. Parenchymal cells (including liver, lung, kidney, adipocytes and muscle) provide the largest tissue mass and principal source of circulating PCT in sepsis. Compared to classical cytokines, the transcriptional expression of Calcitonin-mRNA seemed more uniformely up-regulated. The inflammatory release of PCT can be induced either directly via microbial toxines (eg, endotoxin) or indirectly via a humoural or cell-mediated host response (eg, IL-1ß, TNF-alpha, IL-6). The induction can be attenuated by cytokines also released during a viral infection (eg, interferon-gamma). In sepsis, the predominance of PCT as opposed to mature CT is indicative of a constitutive pathway within cells lacking secretion granules, and, hence, a bypassing of much of the enzymatic processing.
After induction, e.g. by endotoxin, PCT increase is observed within 2-3 hours. Levels then rise rapidly, reaching a plateau after 6-12 hours. PCT concentrations remain high for up to 48 hours, falling to their baseline values within the following 2 days.
PCT plasma concentrations (ng/ml) following infusion of an accidentally bacterially (Acinetobacter baumanii) contaminated infusion solution to a 76 year-old female patient. The induction period can be described according to 2 types of kinetics: during the first phase (<6h), PCT increased by approximately 0.5 ng/ml per hour after a latency phase of about 2-3 hours (first measurable value recorded at time = 3h) followed by massive PCT production at the rate of approximately 50 ng/ml per hour over subsequent hours (Kinetics of procalcitonin in iatrogenic sepsis, 1998.)
After successful treatment intervention the procalcitonin value decreases, indicating a positive prognosis. Persistingly high or even further increasing levels are indicators for poor prognosis. E.g., this has been demonstrated for the monitoring of patients with ventilator-associated pneumonia (VAP).
Typical course of PCT serum level according to patient's response to antibiotic treatment (n=109).
PCT - CLINICAL SIGNIFICANCE
So PCT is useful for its early rise , and so early detection of the infection, for its strict linkage with the severity of the disease and for its role in the prognosis of the disease and the therapeutic monitoring.
Several works shows its high specificity and sensibility in the diagnosis of bacterial meningitis, early detection of sepsis or pyelonephritis, and etiological diagnosis of pneumonia.
A recent study retrospectively analyzed the records of 61 hospitalized patients with community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae or Legionella pneumophila. It was found that serum procalcitonin and sodium concentrations were significantly lower, and ferritin levels were significantly higher, in patients infected with L. pneumophila than in those infected with S. pneumoniae. The ratio of C-reactive protein to procalcitonin significantly distinguished between the groups. High procalcitonin levels were associated with an adverse clinical course.
Guidelines recommend blood culture sampling from hospitalized patients with suspected community-acquired pneumonia (CAP). However, the yield of true-positive results is low. The benefit of procalcitonin was investigated on hospital admission to predict blood culture positivity in CAP.Initial PCT level accurately predicted blood culture positivity in patients with CAP. So PCT measurement has the potential to reduce the number of drawn blood cultures in the emergency department and to implement a more targeted allocation of limited health-care resources.
It is also very useful in the pediatric fields, where we have most of the time a poor semiology and a risky patient.
Procalcitonin levels predict bacteremia in patients with community-acquired pneumonia: a prospective cohort trial.2010
Clinical potential of C-reactive protein and Procalcitonin serum concentrations to guide differential diagnosis and clinical management of pneumococcal and Legionella pneumonia. 2010
Serum procalcitonin in viral and bacterial meningitis. 2011.
Biochemical markers of neonatal sepsis. 2008.
Accuracy of the procalcitonin test in the diagnosis of occult bacteremia in paediatrics: a systematic review and meta-analysis, 2010
Acute serum procalcitonin levels may indicate pyelonephritis in children with febrile UTIs. 2010.
Procalcitonin as a biomarker in respiratory tract infection. 2011.
Comparison of diagnostic performances of various markers for diagnosis of bacterial infection/sepsis
PCT development accurately reflects the progression of the disease - more reliable than other parameters
Summary receiver operating characteristic (SROC) curves comparing serum procalcitonin (PCT) and C-reactive protein (CRP) markers for detection of bacterial infections versus non-infective causes of inflammation. Each point contributing to the SROC curve represents 1 study (total number of studies: 10; total number of patients 905).
Many doctors in the Emergency fields uses CRP to differentiate a bacterial infection vs a viral infection. The problem is that we can find high levels of CRP also in non-severe viral infection, such as the ones due to adenovirus, CMV, influenza virus, measles virus, mumps virus. This is where PCT is useful. Therefore, clinicians should use the PCT results in conjunction with other laboratory findings and clinical signs of the patient and interpret the concrete values in the context with the clinical situation because same focus of infection may be associated with varying individual elevations of PCT concentrations.
Infact optimal cut-off values ranges of Procalcitonin (PCT) are variable and dependent on:
1. the clinical setting (eg, emergency room, ICU, post-operative or trauma patients)
2. the site and extent of the infection (eg, RTI, meningitis, abdominal infection)
3. co-morbidities (eg, immunosuppression)
4. the clinical implications drawn (eg diagnosis, prognosis, antibiotic stewardship)
Increased PCT levels may not always be related to systemic bacterial infection. There are a few situations described where PCT can be elevated by non-bacterial causes. These include, but are not limited to:
1. neonates < 48 hours of life (physiological elevation)
2. the first days after a major trauma, major surgical intervention, severe burns, treatment with OKT3 antibodies and other drugs stimulating the release of pro-inflammatory cytokines
3. patients with invasive fungal infections, acute attacks of plasmodium falciparum malari
4. patients with prolonged or severe cardiogenic shock, prolonged severe organ perfusion anomalies, small cell lung cancer, medullary C-cell carcinoma of the thyroid
So as low PCT levels not always indicate absence of bacterial infection.Falsely low PCT levels in the presence of bacterial infection may accour, for example in case of:
1. early course of infections
2. localised infections
3. subacute infectious endocarditis
PCT – IMPACT ON THERAPEUTIC DECISIONS AND COST REDUCTION
Initial studies on the economic implication of utilizing PCT in the diagnostic process did show that systematic use of Procalcitonin for sepsis diagnosis and monitoring may also have a positive impact on the reduction of antibiotic treatment, therefore allowing a shorter stay in the ICU and lower costs per case and so on with the time a reduction of antibiotic resistance.
PCT management of antibiotic use during an epidemic of enteroviral meningitis: Unnecessary antibiotic treatment was stopped after exclusion of the bacterial infection. The decision to stop antibiotic treatment at a PCT value of < 0.5 ng/mL, without clinical counter-argument (inappropriately pretreated bacterial meningitis excluded), resulted in saving 2.4 days of antibiotics per patient (29.000 j in 2 months).