Procalcitonin in sepsis and systemic inflammation: a harmful biomarker and a therapeutic target

Abstract

The worldwide yearly mortality from sepsis is substantial, greater than that of cancer of the lung and breast combined. Moreover, its incidence is increasing, and its response to therapy has not appreciably improved. In this condition, the secretion of procalcitonin (ProCT), the prohormone of calcitonin, is augmented greatly, attaining levels up to thousands of fold of normal. This hypersecretion emanates from multiple tissues throughout the body that are not traditionally viewed as being endocrine. The serum values of ProCT correlate with the severity of sepsis; they recede with its improvement and worsen with exacerbation. Accordingly, as highlighted in this review, serum ProCT has become useful as a biomarker to assist in the diagnosis of sepsis, as well as related infectious or inflammatory conditions. It is also a useful monitor of the clinical course and prognosis, and sensitive and specific assays have been developed for its measurement. Moreover, it has been demonstrated that the administration of ProCT to septic animals greatly increases mortality, and several toxic effects of ProCT have been elucidated by in vitro experimental studies. Antibodies have been developed that neutralize the harmful effects of ProCT, and their use markedly decreases the symptomatology and mortality of animals that harbour a highly virulent sepsis analogous to that occurring in humans. This therapy is facilitated by the long duration of serum ProCT elevation, which allows for a broad window of therapeutic opportunity. An experimental groundwork has been established that suggests a potential applicability of such therapy in septic humans.

Figure 1

Procalcitonin and its constituent peptides in normal serum, all of which are found at the indicated low concentrations in the blood of normal humans (Snider et al., 1997).

Figure 3

Serial mean serum procalcitonin (ProCT) levels from 19 patients with bacterial endocarditis (Duke classification) who were successfully treated with antibiotics. Within 1 day, ProCT levels had decreased markedly and these values remained close to normal. However, the CRP decline was much more gradual (unpublished data in collaboration with Dr Jonathan Sandoe, Leeds, Great Britain).

Figure 4

Mean peak concentrations of constituent peptides of procalcitonin (ProCT) of several patients with sepsis (G-75 Sephadex gel filtration and C₁₈ reversed-phase high-performance liquid chromatography). The data are expressed in terms of the percentage of the mean peak level of the intact ProCT. In sepsis, some of the ProCT appears to have a two-amino acid truncation at the amino terminus (Weglöhner et al., 2001). The free, amidated, mature calcitonin remains absent or low, because the constitutive secretion of ProCT apparently lacks the enzymatic processing to cleave this peptide from the prohormone.

Figure 5

Study of a trauma patient admitted to the intensive care unit who had an intravascular catheter inserted at day 5 following hospitalization with a consequent risk of ensuing infection (see Maki et al., 2006). Antibiotics were started at day 16 because of the onset of fever, and the catheter was removed a day later. Retrospective studies revealed that on the morning of day 11, procalcitonin (ProCT) suddenly increased from a value that was close to normal (120 pg·mL⁻¹) to 25 000 pg·mL⁻¹, and by that evening had increased further to 60 000 pg·mL⁻¹. However, on the same morning, the CRP had only slightly increased, and then subsequently increased further. Blood cultures remained negative (N) until day 17, when they became positive (P). Thus, the initial alarming increase of serum ProCT had occurred 5 days prior to the clinical diagnosis of catheter-related sepsis.

Figure 6

Illustrative sequence of events by which endotoxin (lipopolysaccharide) from Gram-negative bacteria or other bacterial products, such as lipotechoic acid (LTA) from Gram-positive bacteria (Ryu et al., 2009), interact with immune cells via toll-like receptors (TLRs) to initiate a pro-inflammatory cytokine response that induces the systemic hypersecretion of procalcitonin (ProCT) from parenchymal cells. In turn, in a feedback manner, the blood cell production of these same cytokines may further augment the local levels of ProCT.

Figure 2

Comparative amino acid sequences of procalcitonin (ProCT) of different species. The human prohormone is derived from the CALC-I gene, via an alternative mRNA splicing that gives rise to the inclusion or exclusion of exons (Amara et al., 1982; Becker et al., 2002). The gene produces three different messenger RNAs. Two of these, after translation, eventuate into calcitonin precursor molecules. The first 25 amino acids that reside at the amino terminus of human pre-procalcitonin comprise the hydrophobic signal peptide that directs the prohormone through the endoplasmic reticulum. The following 57 amino acids comprise N-procalcitonin (NProCT), the next 33 amino acid residues is the immature calcitonin (the distal glycine residue is deleted if the calcitonin becomes amidated and is freed from the prohormone). The lysine–arginine at the terminus of NProCT and the lysine–lysine–arginine amino acids at the distal end of calcitonin are basic amino acid sites of cleavage. The 21 amino acid calcitonin carboxypeptide (CCP-I) is at the most distal end of the prohormone. (CCP-II, found in small concentrations in thyroid, pituitary and nervous tissue, differs by eight amino acids). All of the ProCT peptides are freed during the processing of the prohormone. The structure of human ProCT was reported by Dr Le Moullec et al., Paris, France (LeMoullec et al 1984); baboon ProCT was determined by Dr Andrew Russo et al., Iowa City, IA, USA; horse ProCT (Toribio et al., 2003); hamster and porcine ProCT determined by Dr Beat Muller et al., Aarau, Switzerland.