Procalcitonin
Procalcitonin is a peptide precursor of the hormone calcitonin, the latter being involved with calcium homeostasis. It arises once preprocalcitonin is cleaved by endopeptidase. It was first identified by Leonard J. Deftos and Bernard A. Roos in the 1970s. It is composed of 116 amino acids and is produced by parafollicular cells of the thyroid and by the neuroendocrine cells of the lung and the intestine.
The level of procalcitonin in the blood stream of healthy individuals is below the limit of detection of clinical assays. The level of procalcitonin rises in a response to a pro-inflammatory stimulus, especially of bacterial origin. It is therefore often classed as an acute phase reactant. The induction period for procalcitonin ranges from 4–12 hours with a half-life spanning anywhere from 22–35 hours. It does not rise significantly with viral or non-infectious inflammations. In the case of viral infections this is due to the fact that one of the cellular responses to a viral infection is to produce interferon gamma, which also inhibits the initial formation of procalcitonin. With the inflammatory cascade and systemic response that a severe infection brings, the blood levels of procalcitonin may rise multiple orders of magnitude with higher values correlating with more severe disease. However, the high procalcitonin levels produced during infections are not followed by a parallel increase in calcitonin or a decrease in serum calcium levels.
Biochemistry
PCT is a member of the calcitonin superfamily of peptides. It is a peptide of 116 amino acids with an approximate molecular weight of 14.5 kDa, and its structure can be divided into three sections : amino terminus, immature calcitonin, and calcitonin carboxyl-terminus peptide 1. Under normal physiological conditions, active CT is produced and secreted in the C-cells of the thyroid gland after proteolytic cleavage of PCT, meaning, in a healthy individual, that PCT levels in circulation are very low. The pathway for production of PCT under normal and inflammatory conditions are shown in Figure 2. During inflammation, LPS, microbial toxin, and inflammatory mediators, such as IL-6 or TNF-α, induce the CALC-1 gene in adipocytes, but PCT never gets cleaved to produce CT. In a healthy individual, PCT in endocrine cells is produced by CALC-1 by elevated calcium levels, glucocorticoids, CGRP, glucagon, or gastrin, and is cleaved to form CT, which is released to the blood.PCT is located on the CALC-1 gene on chromosome 11. Bacterial infections induce a universal increase in the CALC-1 gene expression and a release of PCT. Expression of this hormone occurs in a site specific manner. In healthy and non-infected individuals, transcription of PCT only occurs in neuroendocrine tissue, except for the C cells in the thyroid. The formed PCT then undergoes post-translational modifications, resulting in the production small peptides and mature CT by removal of the C-terminal glycine from the immature CT by peptidylglycine α-amidating monooxygenase. In a microbial infected individual, non-neuroendocrine tissue also secretes PCT by expression of CALC-1. A microbial infection induces a substantial increase in the expression of CALC-1, leading to the production of PCT in all differentiated cell types. The function of PCT synthesized in nonneuroendocrine tissue due to a microbial infection is currently unknown, but, its detection aids in the differentiation of inflammatory processes.
Diagnostic advantages
Due to PCT's variance between microbial infections and healthy individuals, it has become a marker to improve identification of bacterial infection and guide antibiotic therapy. The table below is a summary from Schuetz, Albrich, and Mueller, summarizing the current data of selected, relevant studies investigating PCT in different types of infections.Legend:
✓ = Moderate evidence in favor of PCT
✓✓ = Good evidence in favor of PCT
✓✓✓ = Strong evidence in favor of PCT
~ = Evidence in favor or against the use of PCT, or still undefined
| Infection Type/Setting | Study Design | PCT Cut-Off | PCT Benefit | Conclusion | References |
| Abdominal Infections | observational | 0.25 | ~ | PCT may help exclude ischemia and necrosis in bowel blockage | |
| Arthritis | observational | 0.1-0.25 | ✓ | PCT differentiates non-infectious arthritis from true infection | |
| Bacteremic infections | observational | 0.25 | ✓✓ | Low PCT levels help rule out microbial infections | |
| Blood stream infection | observational | 0.1 | ✓✓ | PCT differentiates contamination from true infection | |
| Bronchitis | RCT | 0.1-0. 5 | ✓✓✓ | PCT reduces antibiotic exposure without adverse outcomes in the ED | |
| COPD exacerbation | RCT | 0.1-0. 5 | ✓✓✓ | PCT reduces antibiotic exposure without adverse outcomes in the ED and hospital | |
| Endocarditis | observational | 2.3 | ✓ | PCT is an independent predictor with high diagnostic accuracy for acute endocarditis | |
| Meningitis | before-after | 0.5 | ✓ | PCT reduces antibiotic exposure during outbreak of viral meningitis | |
| Neutropenia | observational | 0.1-0.5 | ✓ | PCT is helpful at identifying neutropenic patients with systemic bacterial infection | |
| Pancreatitis | observational | 0.25-0.5 | ~ | PCT correlates with severity and extent of infected pancreatitis | |
| Pneumonia | RCT | 0.1-0. 5; 80-90% ↓ | ✓✓✓ | PCT reduces antibiotic without adverse outcomes exposure in the hospital | |
| Postoperative fever | observational | 0.1-0.5 | ✓ | PCT differentiates non-infectious fever from post-operative infections | |
| Postoperative infections | RCT | 0.5-1.0; 75-85% ↓ | ✓✓ | PCT reduces antibiotic exposure without adverse outcomes in the surgical ICU | |
| Severe sepsis/Shock | RCT | 0.25-0.5; 80-90% ↓ | ✓✓✓ | PCT reduces antibiotic exposure without adverse outcomes in the ICU | |
| Upper respiratory tract infections | RCT | 0.1-0.25 | ✓✓ | PCT reduces antibiotic exposure without adverse outcomes in primary care | |
| Urinary tract infections | observational | 0.25 | ✓ | PCT correlates with severity of urinary tract infections | |
| Ventilator-associated pneumonia | RCT | 0.1-0.25 | ✓✓ | PCT reduces antibiotic exposure without adverse outcomes |
Medical uses
Sepsis
Measurement of procalcitonin can be used as a marker of severe sepsis caused by bacteria and generally grades well with the degree of sepsis, although levels of procalcitonin in the blood are very low. PCT has the greatest sensitivity and specificity for differentiating patients with systemic inflammatory response syndrome from those with sepsis, when compared with IL-2, IL-6, IL-8, CRP and TNF-alpha. Evidence is emerging that procalcitonin levels can reduce unnecessary antibiotic prescribing to people with lower respiratory tract infections. Currently, procalcitonin assays are widely used in the clinical environment.A meta-analysis reported a sensitivity of 76% and specificity of 70% for bacteremia.
A 2018 systematic review comparing PCT and C-reactive protein found PCT to have a sensitivity of 80% and a specificity of 77% in identifying septic patients. In the study, PCT outperformed CRP in diagnostic accuracy of predicting sepsis.
In a 2018 meta-analysis of randomized trials of over 4400 ICU patients with sepsis, researchers concluded that PCT led therapy resulted in lower mortality and lower antibiotic administration.
Organ rejection
Immune responses to both organ rejection and severe bacterial infection can lead to similar symptoms such as swelling and fever that can make initial diagnosis difficult. To differentiate between acute rejection of an organ transplant and bacterial infections, plasma procalcitonin levels have been proposed as a potential diagnostic tool. Typically the levels of procalcitonin in the blood remain below 0.5 ng/mL in cases of acute organ rejection, which has been stated previously to be well below the 1 μg/mL typically seen in bacterial infection.Respiratory illnesses
Given procalcitonin is a blood marker for bacterial infections, evidence shows that it is a useful tool in guiding the initiation and duration of antibiotics in patients with bacterial pneumonia and other acute respiratory infections. The use of procalcitonin guided antibiotic therapy leads to lower mortality, less antibiotic usage, decreased side effects due to antibiotics and promotes good antibiotic stewardship. The value in these protocols are evident since a high PCT level correlates with increased mortality in critically ill pneumonia patients especially those with a low score.In adults with acute respiratory infections, a 2017 systematic review found that PCT-guided therapy reduced mortality, reduced antibiotic use and led to decreased adverse drug effects across a variety of clinical settings.
Procalcitonin-guided treatment limits antibiotic exposure with no increased mortality in patients with acute exacerbation of chronic obstructive pulmonary disease.
Using procalcitonin to guide protocol in acute asthma exacerbation led to reduction in prescriptions of antibiotics in primary care clinics, emergency departments and during hospital admission. This was apparent without an increase in ventilator days or risk of intubation. Be that acute asthma exacerbation is one condition that leads to overuse of antibiotics worldwide, researchers concluded that PCT could help curb over-prescribing.