What is Procalcitonin

Procalcitonin is a substance produced by many types of cells in your body, often in response to bacterial infections but also in response to tissue injury. The level of procalcitonin in your blood can increase significantly in systemic bacterial infections and sepsis. Infections that most commonly lead to sepsis include those of the lung (pneumonia), urinary tract, skin, and digestive tract. Common bacteria that can trigger sepsis include Staphylococcus aureus, Escherichia coli (E. coli), and some types of Streptococcus.

Sepsis is the body’s serious, overwhelming and sometimes life-threatening inflammatory response to a bacterial infection. Normally, a person’s immune system targets an infection, confining the bacteria and limiting its response to the infected area. However, some infections may begin in one site of the body and then spread to the blood (bacteremia) and possibly to other sites. With sepsis, the body produces a generalized inflammatory response to the infection. This can cause a significant rise or fall in body temperature, increased heart rate and breathing rate, and a decrease in blood pressure. If not treated successfully, sepsis can progress to severe sepsis.

Sepsis is more common in newborns, infants, and in the elderly, but other people at risk include post-surgery patients, people with internal medical devices such as catheters, people with chronic conditions such as diabetes, and people with weakened immune systems. Though less common, even healthy children and adults can develop sepsis from an infection that can progress if not recognized early and treated.

Other conditions can also increase procalcitonin in the blood, but usually procalcitonin is only mildly to moderately elevated. Examples of these conditions include tissue damage due to events such as trauma, surgery, pancreatitis, burns, cardiogenic shock (related to a heart attack), acute organ transplant rejection, and kidney involvement in urinary tract infections in children.

You may need procalcitonin test if you have symptoms of sepsis or another serious bacterial infection. These symptoms include:

• Fever and chills
• Sweating
• Confusion
• Extreme pain
• Rapid heartbeat
• Shortness of breath
• Very low blood pressure

Procalcitonin test is usually performed in the hospital. It is mostly used for people who come to the emergency room for treatment and for people who are already in the hospital.

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 procalcitonin 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 procalcitonin measurements ¹.

The cost-effectiveness of procalcitonin 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 procalcitonin 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 procalcitonin assays among septic patients. They determined that procalcitonin 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 procalcitonin assays during their hospital stay. Therefore, clinicians need to use precaution when ordering procalcitonin assays to ensure cost-effective medical practice ².

Procalcitonin Mechanism of Action

Under normal homeostasis, pre-procalcitonin undergoes initial synthesis by thyroid C cells ³. 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 procalcitonin 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 procalcitonin has been found to occur in the liver, pancreas, kidney, lung, intestine and within leukocytes; however, it merits noting that the synthesis of procalcitonin 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 procalcitonin, thus highlighting another advantage of procalcitonin assays ⁴.

KINETICS

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 procalcitonin is between 20 to 24 hours; therefore, when a proper host immune response and antibiotic therapy are in place, procalcitonin levels decrease accordingly by 50% over 24 hours ⁴.

CHEMICAL ASSAYS

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 procalcitonin 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 ⁵.

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 procalcitonin 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 procalcitonin levels display clinical significance when they are in the range of 0.1 to 0.5 ng/mL. Further, research has shown that procalcitonin levels less than 0.1 ng/mL have been shown to have a high negative predictive value (96.3%) for excluding bacterial infections ⁴.

Procalcitonin level

The following clinical scenarios have utilized various procalcitonin cut-off levels to determine the source of an infective process as well as when antibiotic therapy could be utilized/discontinued ⁶.

Once the clinician establishes the cut-off level, it is then important to determine how often procalcitonin measurements should be repeated to determine adequate control. Current clinical data suggests that procalcitonin 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 procalcitonin values be assessed every one to two days to ensure adequate coverage. Further, antibiotic courses should be discontinued as soon as procalcitonin levels drop below 0.1 ng/mL or 80 to 90% below the initial measurement ⁶.

Algorithms have since been established for the emergency department and ICU setting which provide clinicians with a quick method for determining when to initiate or discontinue antibiotics. In the emergency department, 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 procalcitonin levels are above 0.25 ng/mL and that procalcitonin 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 procalcitonin 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 procalcitonin levels drop below 0.5 ng/mL or a decrease of 80% from the peak value. However, if procalcitonin 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 ⁷.

Arthritis

• Procalcitonin cut-off level: 0.1 to 0.25 ng/mL
• Role of procalcitonin: Discriminate infective (septic) arthritis from non-infective arthritis.
• Type of Study: Observational

Bacteremic Infections

• Procalcitonin cut-off level: 0.25 ng/mL
• Role of procalcitonin: To rule out bacteremic infections.
• Type of Study: Observational

Blood Stream Infection (primary)

• Procalcitonin cut-off level: 0.1 ng/mL
• Role of procalcitonin: Differentiate between true infection and a contaminated sample.
• Type of Study: Observational

Bronchitis (acute)/Chronic Obstructive Pulmonary Disease (COPD) Exacerbations

• Procalcitonin cut-off level: 0.1 to 0.5 ng/mL
• Role of procalcitonin: Reduce (unnecessary) antibiotic exposure in the ED and inpatient setting without adverse outcomes.
• Type of Study: Randomized Control Trial

Endocarditis

• Procalcitonin cut-off level: 2.3 ng/mL
• Role of procalcitonin: High diagnostic accuracy for predicting acute endocarditis.
• Type of Study: Observational

Meningitis

• Procalcitonin cut-off level: 0.5 ng/mL
• Role of procalcitonin: Differentiate viral from bacterial meningitis and subsequently reduced antibiotic exposure.
• Type of Study: Before-After

Neutropenia

• Procalcitonin cut-off level: 0.1 to 0.5 ng/mL
• Role of procalcitonin: Identify systemic bacterial infections within neutropenic patients.
• Type of Study: Observational

Pneumonia

• Procalcitonin cut-off level: 0.1 to 0.5 ng/mL
• Role of procalcitonin: Reduce antibiotic exposure during hospitalization without adverse outcomes.

Postoperative Fever

• Procalcitonin cut-off level:0.1 to 0.5 ng/mL
• Role of procalcitonin: Differentiate post-operative infections from non-infectious fever.
• Type of Study: Observational

Postoperative Infections

• Procalcitonin cut-off level: 0.5 to 1.0 ng/mL
• Role of procalcitonin: Minimize antibiotic treatment in surgical ICU without detrimental outcomes.
• Type of Study: Randomized Control Trial

Severe Sepsis/Shock

• Procalcitonin cut-off level: 0.25 to 0.5 ng/mL
• Role of procalcitonin: Limit antibiotic treatment in the ICU without detrimental outcomes.
• Type of Study: Randomized Control Trial

Upper Respiratory Tract Infections

• Procalcitonin cut-off level: 0.1 to 0.25 ng/mL
• Role of procalcitonin: Limit antibiotic treatment in the ICU without detrimental outcomes.
• Type of Study: Randomized Control Trial

Urinary Tract Infections

• Procalcitonin cut-off level: 0.25 ng/mL
• Role of procalcitonin: Determine the extent of renal involvement.
• Type of Study: Observational

Ventilator-Associated Pneumonia

• Procalcitonin cut-off level: 0.1 to 0.25 ng/mL ⁶
• Role of procalcitonin: Minimize antibiotic treatment without detrimental outcomes.
• Type of Study: Randomized Control Trial

Procalcitonin test

Procalcitonin test measures the level of procalcitonin in your blood. The procalcitonin test can help your health care provider determine if you have sepsis or severe bacterial infections in the early stages and to distinguish between a bacterial infection and other non-bacterial causes of signs and symptoms in a seriously ill person. This may help you get treated promptly and avoid life-threatening complications. Procalcitonin testing is often done in serious and emergency cases, so results may be available within an hour or so.

A high procalcitonin level could be a sign of a serious bacterial infection, such as sepsis. Sepsis is the body’s severe response to infection. Sepsis happens when an infection in one area of your body, such as your skin or urinary tract, spreads into your bloodstream. This triggers an extreme immune reaction. Sepsis can cause a rapid heartbeat, shortness of breath, decreased blood pressure, and other symptoms. Without quick treatment, sepsis can lead to organ failure or even death.

A procalcitonin test may be used to help:

• Diagnose sepsis and other bacterial infections, such as meningitis
• Differential diagnosis of bacterial versus viral meningitis
• Differential diagnosis of community-acquired bacterial versus viral pneumonia
• Diagnosis of bacteremia and septicemia in adults and children (including neonates)
• Diagnose kidney infections in children with urinary tract infections
• Diagnosis of bacterial infection in neutropenic patients
• Determine the severity of a sepsis infection
• Find out whether an infection or illness is caused by bacteria
• Monitor the effectiveness of antibiotics therapy
• Diagnosis, risk stratification, and monitoring of septic shock
• Diagnosis of systemic secondary infection post-surgery, and in severe trauma, burns, and multiorgan failure

The procalcitonin test is not considered a replacement for the performance of other laboratory tests. Rather, it provides additional information that may allow appropriate treatment to be initiated or discontinued sooner.

Early detection of systemic bacterial infections, including bacterial pneumonia and bacterial meningitis, is important because they can be life-threatening and can be readily treated. However, the use of antibiotics in non-bacterial conditions may cause delays in proper treatment and can lead to more antibiotic-resistant bacteria.

The procalcitonin test is being studied in additional populations, expanding beyond critically ill ICU patients. As more data are gathered, its clinical usefulness will be better understood and its intended use(s) more fully defined.

What happens during a procalcitonin test?

A health care professional will take a blood sample from a vein in your arm, using a small needle. After the needle is inserted, a small amount of blood will be collected into a test tube or vial. You may feel a little sting when the needle goes in or out. This usually takes less than five minutes.

Will I need to do anything to prepare for the procalcitonin test?

You don’t need any special preparation for a procalcitonin test.

How is procalcitonin test used?

Procalcitonin tests are not as precise as other laboratory tests for infections. So your health care provider will need to review and/or order other tests before making a diagnosis. But a procalcitonin test does offer important information that can help your provider start treatment sooner and may help you avoid serious illness.

The procalcitonin test may be used, along with other tests and examinations, to help detect or rule out sepsis in a seriously ill person. It has primarily been used in people who seek care at emergency departments or who are admitted to intensive care units (ICUs) with signs and symptoms that may be due to sepsis.

The procalcitonin test may be used to help:

• Determine the risk that a critically ill person will progress to severe sepsis and septic shock, or the risk of the person dying
• Distinguish between bacterial and non-bacterial causes of infections, such as meningitis and pneumonia
• Diagnose kidney infections in children with urinary tract infections
• Detect the development of a secondary bacterial infection in a person who has tissue damage due to trauma or surgery, or a viral illness such as pneumonia
• Guide antibiotic treatment and/or monitor effectiveness—the test may be used in helping to decide whether antibiotics should be started or stopped for patients with lower respiratory infections and whether antibiotics can be discontinued in patients with sepsis

Examples of other tests that may be used along with procalcitonin include C-reactive protein (CRP), cultures (e.g., blood culture, urine culture), lactate, blood gases, complete blood count (CBC), and cerebrospinal fluid (CSF) analysis.

When is procalcitonin test ordered?

The procalcitonin test may be ordered when a seriously ill person has signs and symptoms that suggest a systemic or severe bacterial infection and/or sepsis. Signs and symptoms of sepsis may include:

• Chills, shivering, fever
• Clammy or sweaty skin
• Extreme pain or discomfort
• Rapid breathing
• Rapid heartbeat
• Confusion or disorientation
• Less frequent urination

Procalcitonin test may be ordered when a person has an infection, like pneumonia or meningitis, and it is not known whether the cause is bacterial or non-bacterial. Sometimes the test may be ordered when a child has signs and symptoms that suggest a urinary tract infection.

A series of procalcitonin tests may be ordered at intervals when a healthcare practitioner wants to monitor antibiotic treatment and/or decide whether treatment can be safely discontinued.

The test may occasionally be ordered when someone has tissue damage from trauma, surgery, or a burn, or a viral illness such a pneumonia and a healthcare practitioner suspects that the person may have developed a secondary bacterial infection.

Procalcitonin normal levels

• Adults and children > or =72 hours: < or =0.15 ng/mL
• Children < 72 hours: <2.0 ng/mL at birth, rises to < or =20 ng/mL at 18-30 hours of age, then falls to < or =0.15 ng/mL by 72 hours of age

General considerations:

• In children older than 72 hours and in adults, levels below 0.15 ng/mL make a diagnosis of significant bacterial infection unlikely.
• Procalcitonin between 0.15 and 2.0 ng/mL do not exclude an infection, because localized infections (without systemic signs) may be associated with such low levels.
• Levels above 2.0 ng/mL are highly suggestive of systemic bacterial infection/sepsis or severe localized bacterial infection, such as severe pneumonia, meningitis, or peritonitis. They can also occur after severe noninfectious inflammatory stimuli such as major burns, severe trauma, acute multiorgan failure, or major abdominal or cardiothoracic surgery. In cases of noninfectious elevations, procalcitonin levels should begin to fall after 24 to 48 hours.
• Autoimmune diseases, chronic inflammatory processes, viral infections, and mild localized bacterial infections rarely lead to elevations of procalcitonin of more than 0.5 ng/mL.

Procalcitonin responses in neutropenic patients are similar to patients with normal neutrophil counts and function, and the cutoffs discussed under general considerations above should be used.

What does procalcitonin test result mean?

Procalcitonin results are interpreted in conjunction with findings from clinical evaluations as well as other laboratory tests.

Low procalcitonin

Low levels of procalcitonin in a seriously ill person may indicate a low risk of developing sepsis and progression to severe sepsis and/or septic shock but do not exclude it.

Low levels of procalcitonin may indicate that the person’s symptoms are due to a cause other than a bacterial infection, such as a viral infection. A low level may also indicate a localized infection that has not spread or become systemic, or a systemic infection that is less than six hours old.

High procalcitonin

Very high levels of procalcitonin can be seen with medullary thyroid cancer, but the test is not used to diagnose or monitor this condition.

High levels of procalcitonin indicate a high probability of sepsis and also suggest a higher risk of progression to severe sepsis and septic shock. High levels may also been seen in people with serious bacterial infections, such as meningitis.

Moderate procalcitonin elevations may be due to a non-infectious condition or due to an early infection and, along with other findings, should be reviewed carefully. They may also be seen in children with kidney infections.

Decreasing procalcitonin levels over time in a person being treated for sepsis or a bacterial infection indicate a response to therapy. Stable or increasing procalcitonin levels may indicate the need for continued therapy.

Diagnosis of bacteremia in neonates

After birth procalcitonin values increase from birth to reach peak values at about 24 hours of life and the decrease gradually by 48 hours of life. Therefore, during the first 72 hours of life different reference ranges will apply to newborn infants at different hours of age. procalcitonin levels on newborns suffering from early sepsis are significantly higher than those of noninfected newborns when reference ranges by hours of age are used.(1,2) Adult levels should apply at 72 hours or more after birth.

Diagnosis of renal involvement in pediatric urinary tract infections

In children with urinary tract infections, a procalcitonin level above 0.5 ng/mL has a 70% to 90% sensitivity and an 80% to 90% specificity for renal involvement.

In the appropriate clinical setting, procalcitonin levels above 2.0 ng/mL on the first day of admission to the intensive care unit (ICU) represent a high risk for progression to severe sepsis and/or septic shock. procalcitonin levels below 0.5 ng/mL on the first day of ICU admission represent a low risk for progression to severe sepsis and/or septic shock. Reported sensitivity and specificity for the diagnosis of sepsis range from 60% to 100%, depending on underlying and coexisting diseases and the patient populations studied. The higher the procalcitonin level the worse the prognosis.

A procalcitonin level below 0.5 ng/mL makes bacterial meningitis very unlikely. Most patients with bacterial meningitis will have procalcitonin levels of more than 10 times this level.

With successful antibiotic therapy, procalcitonin levels should fall with a half-life to 24 to 35 hours.

Cautions

Severe trauma, major burns, multiorgan failure, or major surgery can cause procalcitonin elevations in the absence of sepsis. After removal of the noxious stimulus, procalcitonin should start to fall.

Patients with untreated end-stage renal failure may have procalcitonin levels greater than 0.15 ng/mL in the absence of infection or severe inflammation. Within 3 hemodialysis treatments this should fall to the normal reference range. End-stage renal failure patients on stable hemodialysis or peritoneal dialysis treatments have procalcitonin levels similar to healthy adults with normal renal function.

Patients with medullary thyroid carcinoma or, very rarely, islet cell tumors may have significant elevations in procalcitonin in the absence of sepsis. In certain cases, these levels may exceed 10,000 ng/mL.

Some infants and children may have procalcitonin levels from 0.15 ng/mL to 0.50 ng/mL for unknown reasons.

As with all immunometric assays, there is a low, but definite possibility of false-positive results in patients with heterophile antibodies. Test results that do not fit the clinical picture should therefore be discussed with the laboratory.

A hook effect can occur at procalcitonin concentrations above 2,500 ng/mL (extremely rare), resulting in a lower measured procalcitonin concentration than is actually contained in the specimen. This may complicate the interpretation of serial procalcitonin measurements in rare patients with extremely high procalcitonin levels. If there is clinical suspicion of this occurring, then retesting after specimen dilution should be requested.

Note: A “high-dose hook” effect was observed in a patient specimen with a procalcitonin concentration of 10,270 ng/mL (calcitonin 313,600 pg/mL). This specimen appeared to have a procalcitonin value of only 2.8 ng/mL when measured without dilution.

What other tests may be done if a systemic bacterial infection or sepsis is suspected?

Other tests may include cultures (e.g., blood culture, urine culture or cultures of other body fluids), complete blood count (CBC), lactate, blood gases, comprehensive metabolic panel (CMP), prothrombin time (PT) and/or partial thromboplastin time (PTT) and C-reactive protein (CRP).

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