Procalcitonin (PCT) is a
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
...
precursor
Precursor or Precursors may refer to:
* Precursor (religion), a forerunner, predecessor
** The Precursor, John the Baptist
Science and technology
* Precursor (bird), a hypothesized genus of fossil birds that was composed of fossilized parts of u ...
of the hormone
calcitonin
Calcitonin is a 32 amino acid peptide hormone secreted by parafollicular cells (also known as C cells) of the thyroid (or endostyle) in humans and other chordates. in the ultimopharyngeal body. It acts to reduce blood calcium (Ca2+), opposing th ...
, the latter being involved with
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
homeostasis
In biology, homeostasis (British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and ...
. It arises once preprocalcitonin is cleaved by
endopeptidase
Endopeptidase or endoproteinase are proteolytic peptidases that break peptide bonds of nonterminal amino acids (i.e. within the molecule), in contrast to exopeptidases, which break peptide bonds from end-pieces of terminal amino acids. For this ...
. It was first identified by Leonard J. Deftos and Bernard A. Roos in the 1970s. It is composed of 116
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
s and is produced by
parafollicular cell
Parafollicular cells, also called C cells, are neuroendocrine cells in the thyroid. The primary function of these cells is to secrete calcitonin. They are located adjacent to the thyroid follicles and reside in the connective tissue. These cells a ...
s (C cells) of the
thyroid
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...
and by the
neuroendocrine cell
Neuroendocrine cells are cells that receive neuronal input (through neurotransmitters released by nerve cells or neurosecretory cells) and, as a consequence of this input, release messenger molecules (hormones) into the blood. In this way they bri ...
s of the lung and the intestine.
The level of procalcitonin in the blood stream of healthy individuals is below the limit of detection (0.01 µg/L) of clinical assays.
The level of procalcitonin rises in a response to a pro-inflammatory stimulus, especially of
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...
l 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 virus infections this is due to the fact that one of the cellular responses to a viral infection is to produce
interferon gamma
Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheeloc ...
, which also inhibits the initial formation of procalcitonin.
With the inflammatory cascade and systemic response that a severe
infection
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dis ...
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
![Production Pathway of PCT and CT in healthy and infected individuals](https://upload.wikimedia.org/wikipedia/commons/0/02/Production_Pathway_of_PCT_and_CT_in_healthy_and_infected_individuals.png)
PCT is a member of the
calcitonin
Calcitonin is a 32 amino acid peptide hormone secreted by parafollicular cells (also known as C cells) of the thyroid (or endostyle) in humans and other chordates. in the ultimopharyngeal body. It acts to reduce blood calcium (Ca2+), opposing th ...
(CT) superfamily of
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
...
s. It is a peptide of 116 amino acid with an approximate molecular weight of 14.5 kDa, and its structure can be divided into three sections
see Figure 1:
amino terminus (represented by the ball and stick model in Figure 1), immature calcitonin (shown in Figure 1 from PDB as the crystal structure of procalcitonin is not yet available), 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 (<.05 ng/mL).
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 adipoctyes, 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
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
11.
Bacterial infections induce a universal increase in the CALC-1 gene expression and a release of PCT (>1 μg/mL).
Expression of this hormone occurs in a site specific manner.
In healthy and non-infected individuals, transcription of PCT only occurs in
neuroendocrine
Neuroendocrine cells are cells that receive neuronal input (through neurotransmitters released by nerve cells or neurosecretory cells) and, as a consequence of this input, release messenger molecules (hormones) into the blood. In this way they bri ...
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 (PAM). 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
Medical uses
Sepsis
Measurement of procalcitonin can be used as a marker of severe
sepsis
Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...
caused by bacteria and generally grades well with the degree of sepsis, although levels of procalcitonin in the
blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the cir ...
are very low. PCT has the greatest
sensitivity (90%) and
specificity (91%) for differentiating patients with
systemic inflammatory response syndrome
Systemic inflammatory response syndrome (SIRS) is an inflammatory state affecting the whole body. It is the body's response to an infectious or noninfectious insult. Although the definition of SIRS refers to it as an "inflammatory" response, i ...
(SIRS) from those with sepsis, when compared with
IL-2
The Ilyushin Il-2 (Russian: Илью́шин Ил-2) is a ground-attack plane that was produced by the Soviet Union in large numbers during the Second World War. The word ''shturmovík'' ( Cyrillic: штурмовик), the generic Russian term ...
,
IL-6,
IL-8,
CRP and
TNF-alpha
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
. Evidence is emerging that procalcitonin levels can reduce unnecessary antibiotic prescribing to people with
lower respiratory tract infection
Lower respiratory tract infection (LRTI) is a term often used as a synonym for pneumonia but can also be applied to other types of infection including lung abscess and acute bronchitis. Symptoms include shortness of breath, weakness, fever, cough ...
s.
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 (CRP) 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
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient a ...
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
Bacterial pneumonia is a type of pneumonia caused by bacterial infection.
Types
Gram-positive
'' Streptococcus pneumoniae'' () is the most common bacterial cause of pneumonia in all age groups except newborn infants. ''Streptococcus 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 Antimicrobial stewardship is the systematic effort to educate and persuade prescribers of antimicrobials to follow evidence-based prescribing, in order to stem antimicrobial overuse, and thus antimicrobial resistance. AMS has been an organized effo ...
.
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 lo
CURB-65 pneumonia risk factorscore.
In adults with acute respiratory infections, a 2017 systematic review found that PCT-guided therapy reduced mortality, reduced antibiotic use (2.4 less days of antibiotics) and led to decreased
adverse drug effects across a variety of clinical settings (ED, ICU, primary care clinic).
Procalcitonin-guided treatment limits antibiotic exposure with no increased mortality in patients with acute exacerbation of
chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce ...
.
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
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...
exacerbation is one condition that leads to overuse of antibiotics worldwide, researchers concluded that PCT could help curb over-prescribing.
Cardiovascular disease
PCT serves a marker to help differentiate acute respiratory illness such as infection from an acute cardiovascular concern. It also has value as a prognostic lab value in patients with
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...
or
coronary heart disease
Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pl ...
as its levels correlate with the severity of the illness.
The
European Society of Cardiology
The European Society of Cardiology (ESC) is an independent non-profit, non-governmental professional association that works to advance the prevention, diagnosis and management of diseases of the heart and blood vessels, and improve scientific un ...
recently released a PCT-guided algorithm for administering antibiotics in patients with
dyspnea
Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing di ...
and suspected acute
heart failure. The guidelines use a cut off point of .2 ng/mL and above as the point at which to give antibiotics. This coincides with a 2017 review of literature which concluded that PCT can help reduce antibiotic overuse in patients presenting with acute heart failure. In regards to mortality, a meta analysis of over 5000 patients with heart failure concluded that elevated PCT was reliable in predicting short term mortality.
Meningitis
Blood procalcitonin levels can help confirm
bacterial meningitis
Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, headache, and neck stiffness. Other symptoms include confusion or ...
and. if negative, can effectively rule out bacterial meningitis. This was shown in a review of over 2000 patients in which PCT had a sensitivity of 86% and a specificity of 80% for
cerebrospinal fluid
Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates.
CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...
PCT. Blood PCT measurements proved superior to cerebrospinal fluid PCT with a sensitivity of 95% and a specificity of 97% as a marker for bacterial meningitis.
In acute meningitis, serum PCT is useful as a biomarker for sepsis. It can also be of use in determining viral meningitis versus bacterial meningitis. These findings are the result of a 2018 literature review. This followed a 2015 meta analysis that showed that PCT had a sensitivity of 90% and a specificity of 98% in judging viral versus bacterial meningitis. PCT also outperformed other biomarkers such as C-reactive protein.
Gastrointestinal disease
Evidence shows that an elevated PCT above .5 ng/mL could help diagnose infectious complications of
inflammatory bowel disease such as abdominal abscesses, bacterial
enterocolitis
Enterocolitis is an inflammation of the digestive tract, involving enteritis of the small intestine and colitis of the colon. It may be caused by various infections, with bacteria, viruses, fungi, parasites, or other causes. Common clinical manif ...
etc. PCT can be effective in early recognition of infections in IBD patients and decisions on whether to prescribe antibiotics.
Kidney disease
Patients with chronic kidney disease and end-stage renal disease are at higher risk for infections, and procalcitonin has been studied in these populations, who often have higher levels. Procalcitonin can be dialyzed, and so levels are dependent upon when patients receive
hemodialysis
Hemodialysis, also spelled haemodialysis, or simply dialysis, is a process of purifying the blood of a person whose kidneys are not working normally. This type of dialysis achieves the extracorporeal removal of waste products such as creatinin ...
. While there is no formally accepted cutoff value for patients undergoing HD, using a value of greater or equal to 0.5 ng/mL yielded a sensitivity of 97-98% and a specificity of 70-96%.
Hepatitis
PCT, possibly together with
CRP, is used to corroborate the
MELD score.
Septic arthritis
PCT at a cutoff value of .5 ng/mL was effective at ruling in
septic arthritis
Acute septic arthritis, infectious arthritis, suppurative arthritis, osteomyelitis, or joint infection is the invasion of a joint by an infectious agent resulting in joint inflammation. Generally speaking, symptoms typically include redness, h ...
in an analysis of over 8000 patients across 10 prospective studies. PCT had a sensitivity of 54% and specificity of 95%. The study also concluded that PCT outperforms
C-reactive protein
C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin- ...
in differentiating septic arthritis from non-septic arthritis.
Cancer
A 2016 literature review showed that PCT has good value in diagnosing infections in oncologic patients. Moreso, it is especially effective in diagnosing major life threatening episodes in cancer patient such as bacteremia and sepsis. Procalcitonin is reliable to monitor recurrence of
medullary thyroid carcinoma
Medullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells (C cells), which produce the hormone calcitonin.Hu MI, Vassilopoulou-Sellin R, Lustig R, Lamont JP"Thyroid and Parathyroid Cancers"in Pazdur R, ...
. In detecting cancer recurrence, PCT had a sensitivity and specificity of 96% and 96% respectively.
Pediatrics
In a meta analysis of 17 studies, PCT had a sensitivity of 85% and a specificity of 54% in diagnosing sepsis in neonates and children. The PCT cut off used was between 2-2.5 ng/mL.
In children presenting with fever without an apparent source, a PCT level of .5 ng/mL had a sensitivity of 82% and specificity of 86%. At a 5 ng/mL value, the sensitivity and specificity were 61% and 94%. PCT can help the clinical decision making while identifying invasive bacterial infection in children with unexplained fever.
PCT levels correlate with the degree of illness in pediatric patients with sepsis or
urinary tract infection
A urinary tract infection (UTI) is an infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (cystitis) and when it affects the upper urinary tract it is known as a kidne ...
s making it effective as a prognostic lab value in these patients.
Antibiotic stewardship
Procalcitonin guided cessation of antibiotic use reduces duration of
antibiotic exposure and lowers mortality in critically ill patients in the
Intensive Care Unit
220px, Intensive care unit
An intensive care unit (ICU), also known as an intensive therapy unit or intensive treatment unit (ITU) or critical care unit (CCU), is a special department of a hospital or health care facility that provides intensi ...
.
In adult emergency department patients with respiratory tract illnesses, PCT-guided treatment groups had reduced antibiotic use. PCT references ranges are also used to determine the likelihood a patient has systemic infection (sepsis), thereby reducing incidence of unnecessary antibiotic use in cases where sepsis is unlikely.
PCT and amphetamines
Excessive overdose on
amphetamine or
its analogs can induce systemic inflammation; in a case report of amphetamine overdose, sans bacterial infection, significant elevations in procalcitonin were observed.
References
External links
Procalcitonin: analyte monograph- The Association for Clinical Biochemistry and Laboratory Medicine
{{Infectious blood tests
Peptides
Blood tests
Diagnostic intensive care medicine
Immunologic tests
Precursor proteins