Procalcitonin (PCT) is the precursor of calcitonin (CT), a hormone that originates in the thyroid gland and reduces blood calcium. The importance of CT in humans is still not well established, compared with its importance in various animal species.¹ This is interesting when juxtaposed with the role its precursor PCT plays in diagnosing infections in hospitals all over the world (see Figure 1). PCT has been a valuable marker for bacterial sepsis for nearly two decades, ever since it was initially discovered that PCT levels increased exponentially during bacterial infections and that there was a correlation between the amount of PCT increase and severity of the infection.²
In most hospital cases, sepsis occurs as a result of a bacterial infection, leading to bacteremia. The infection travels through the bloodstream, spreading to other organs. The resulting condition is characterized by some or all of the systemic

Figure 1: Use of procalcitonin in patients who are presented to the emergency department at risk for respiratory infection.

inflammatory response syndrome (SIRS) criteria as the body’s immune system responds to the infection in the blood. Severe sepsis can lead to organ dysfunction, hypoperfusion, and hypotension. The most severe cases of sepsis can lead to septic shock, multiple organ dysfunction, and death. Every year, approximately 750,000 patients in the United States are infected with sepsis.³ It has been reported that 28-50% of those infected with sepsis die.⁴
The SIRS criteria were established in 1992 as part of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. The SIRS criteria include the following:

·     Body temperature lower than 36°C or higher than 38°C;
·     heart rate greater than 90 beats per minute;
·     tachypnea (high respiratory rate) with more than 20 breaths per minute, or an arterial partial pressure of carbon dioxide less than 4.3 kPa (32 mmHg);
·     white blood cell count less than 4000 cells/mm3 (4 × 109 cells/L) or greater than 12,000 cells/mm3 (12 × 109 cells/L); or the presence of greater than 10% immature neutrophils (band forms).

While certainly helpful, the SIRS criteria are insufficient to diagnose sepsis accurately. Such diagnosis of sepsis lacks specific clinical signs and symptoms. Clinical and SIRS criteria alone are not accurate enough to provide a reliable diagnosis and are limited in making therapeutic decisions. Microbiological cultures require significant amounts of time, do not reflect the host response of systemic inflammation or the onset of organ dysfunction, and may not be definitive in septic patients for a number of reasons (see Figure 2).⁵
IVD tests to detect PCT in patients enable care providers to identify the presence of bacterial infection more quickly, meaning the marker holds tremendous potential to greatly decrease morbidity and mortality associated with sepsis.⁶ Because PCT levels in the blood increase when an infection is present, and the amount of PCT increase correlates closely to the severity of

Figure 2: Use of procalcitonin in patients in the intensive care unit.

the infection, tracking PCT presents a quicker, more reliable method for diagnosing sepsis compared to the SIRS criteria.
With a simple bedside test, healthcare workers can quickly ascertain PCT levels in patient blood. Physicians around the world are using the PCT assay to diagnose and treat sepsis successfully, and to help in diagnosing other bacterial infections, notably those that attack the lower respiratory tract.⁷ The future is bright for expanding the application of the PCT assay, with 71 documented clinical trials currently occurring in the United States investigating the role of PCT as a potential marker for infections, including several different pneumonias, appendicitis, and meningitis. Studies are also being done to see what PCT can do in terms of diagnosing various post-surgical events, ranging from general post-surgical infections to infections specific to patients undergoing pediatric heart surgery.

Discovery of PCT

In 1993, researchers first noted that the levels of PCT present in the blood were much higher than normal during infections.⁸ Increased levels of PCT indicated a bacterial infection accompanied by a systemic inflammatory reaction. Localized infections caused minor increases in PCT, while sometimes exponentially higher PCT values were observed during acute disease conditions accompanied by more severe systemic reactions to infection (i.e., severe sepsis or septic shock).
As stated earlier, the typical prognosis for patients suffering from sepsis is not good, with as many as half of them succumbing to the infection. The earlier sepsis is diagnosed, the better the outcome will be. However, sepsis has been difficult to distinguish from other common diseases in critically ill patients, many of which are non-infectious conditions that show signs of acute inflammation but negative microbiological test results. Therefore, the potential to test patients for the presence of PCT gave hope for a systematic hastening of sepsis diagnoses and improved survival.
Researchers investigating the prohormone quickly found that PCT levels are very low during non-bacterial infections, more chronic inflammatory disorders, or autoimmune events. However, PCT levels increased markedly with bacterial infections and exponentially with sepsis.
In a 2001 study of inflammatory markers in which the accuracy of sepsis diagnosis was based on clinical models with and

Figure 3: Procalcitonin cut-offs depend on the severity of infection and the risk to patients.

without PCT, PCT was the only marker that made a significant contribution to the clinical diagnosis of sepsis. In the study, PCT yielded the highest discriminative value: a sensitivity of 97% and a specificity of 78% in differentiating between patients meeting the SIRS criteria from those with sepsis-related conditions. The study concluded that adding PCT to a model based solely on standard indicators significantly improved (likelihood ratio test: p=0.001) the predictive power of detecting sepsis, increasing the area under the receiver operating characteristic curves (AUC) value for the routine-based model from 0.77 to 0.94.⁹
Since this initial discovery, PCT has been accepted as an effective and reliable marker for sepsis, and not long afterward, a formal test, the PCT assay, was created.² First used in Europe in the early 1990s, the PCT assay quickly became a standard protocol for sepsis testing throughout Europe. Soon after, because of the more open process for approving diagnostic tests in Europe, the PCT assay was used for diagnosing a wide spectrum of hospital-acquired infections, and other conditions.

Testing for Infection

Lower respiratory tract infections (LRTI) account for nearly 10% of the morbidity and mortality worldwide. As much as 75% of all antibiotic doses are prescribed for acute respiratory-tract infections, despite the fact that a majority of the cases are viral rather than bacterial. This inappropriate use of antibiotics is believed to be a major cause of the increase in antibiotic-resistant bacteria.
In a 2004 study, PCT was used to guide antibiotic therapy in patients suspected of having LRTI. In the PCT-guided patients, antibiotic use was significantly reduced. The adjusted relative risk of antibiotic exposure for the PCT-guided patients was 0.49 compared to the non-PCT-guided patients. The study concluded that withholding antibiotic treatment based on PCT guidance did not compromise outcomes.⁷ Aside from any benefits derived via antibiotic use in this case, the more direct clinical result of the study was that PCT was shown to be a reliable marker for LRTI. The following are other similar clinical conditions in which PCT was used successfully for specific patient populations.

Chronic Obstructive Pulmonary Disease

Affecting approximately 16 million adults in the United States, chronic obstructive pulmonary disease (COPD) is one of the fastest growing causes of morbidity and death.^5,8 Antibiotic therapy results in recovery only in selected COPD cases, since only rare cases are caused by bacterial infection.¹⁰
A 2007 study of patients experiencing exacerbations of COPD concluded that PCT guidance reduced antibiotic prescription compared to non-PCT-guided therapy (40% and 72%, respectively) and showed a sustained reduction in total antibiotic exposure for up to six months with no compromise in clinical symptoms and recovery of lung function.¹⁰ The effectiveness of PCT in guiding therapy points to its usefulness as a marker for COPD.

Community-Acquired Pneumonia

Community-acquired pneumonia (CAP) is a common and serious medical condition. In bacterial CAP, early initiation of therapy is critical, since a delay of more than four hours can result in increased mortality.¹¹ The optimal treatment duration is currently unknown.¹² In a 2006 study, PCT was used to help guide the initiation and duration of antibiotic treatment of patients suspected of having CAP. The PCT guidance reduced total antibiotic exposure by 0.52 and shortened antibiotic treatment duration to a median five days, compared to 12 days for the non-PCT-guided patients.¹³
In a study of emergency department patients suspected of having CAP, PCT levels of 0.5 and above correlated with a higher incidence of positive culture and severe sepsis development. PCT levels of less than 0.1 had the lowest mortality, independent of clinical parameters.¹⁴ Another emergency department study found that a PCT level of less than 0.1 virtually excluded the risk for bacteremia in patients suspected of having CAP.¹⁵

Ventilator-Associated Pneumonia

Ventilator-associated pneumonia (VAP) is the most frequent nosocomial infection among ICU patients on mechanical ventilation and is associated with prolonged hospital stays and higher ICU mortality.¹⁶ In a study of ICU patients with VAP, the PCT levels in all patients were measured on days one, three, and seven. The PCT levels were significantly higher on day seven compared to day one in patients with unfavorable outcomes. The study concluded that PCT is a strong predictor of VAP outcomes.¹⁷ Another study found that with PCT monitoring, the number of antibiotic-free days after VAP onset increased considerably (13 days versus 9.5 days), which translated into a reduction in the overall duration of antibiotic therapy.¹⁸

Neonates and Children

Sepsis is a major problem in neonatal intensive care units (NICU). Early sepsis detection in neonates is challenging because the signs of sepsis are similar to other non-infectious conditions in neonates. Studies have shown PCT to be useful in identifying sepsis in neonates and children. One meta-analysis points out that the kinetics of PCT follow a similar pattern in children and adults, with some evidence that PCT levels vary in a similar way during the first 48 hours after birth.¹⁹
In one study of critically ill NICU patients, PCT demonstrated a sensitivity of 85.7% (versus 46.4% for C-reactive protein) and a specificity of 97.5% for early onset infections within the first 48 hours after birth. For late onset infections after the first 48 hours, PCT demonstrated a sensitivity and specificity of 100%.¹⁹
A study of pediatric emergency patients found that PCT is a better marker than C-reactive protein for invasive infections with a sensitivity of 91.3% and a specificity of 93.5%, versus 78% and 75%, respectively, for C-reactive protein. The study concluded that PCT enables early detection of bacterial infections even in cases in which the evolution of fever is less than 12 hours.²⁰

Severe Burns and Trauma

Identifying sepsis in burn patients can be especially challenging, since the signs of sepsis can be present in the absence of infection.²¹ Likewise, in trauma patients, the classic SIRS criteria are often present but are not always useful in predicting infection.²² PCT can be helpful in identifying sepsis in these patient populations.
In a study of burn victims with and without sepsis, PCT demonstrated a sensitivity of 100% and a specificity of 89.3%, with an AUC of 0.97 in diagnosing sepsis. Non-burn survivors had mean PCT levels significantly higher than that of survivors. Meanwhile, C-reactive protein, erythrocyte sedimentation rate, and white blood cell count had little diagnostic value.²¹
A study of trauma patients observed early and significant increases in PCT levels when septic complications emerged. The study also found that PCT marked possible septic complications during SIRS after a major trauma and that high PCT concentrations in ICU patients at admission indicated an increased risk of septic complications. The AUC in diagnosing sepsis at admission was 0.787 for PCT and 0.489 for C-reactive protein.²²

Organ Transplants

Infection and organ rejection are the most common complications following organ transplants. Early diagnosis is important to determine the appropriate treatments.²³
In a study of liver transplant patients, PCT was used to differentiate between infection and organ rejection in post-transplant patients with fevers of unknown origin. The study observed an increase in the PCT levels in patients with infectious complications and observed no PCT increase in patients who experienced an organ rejection episode. The study concluded that in cases involving a fever of unknown origin with no rise in PCT levels, organ rejection may be suspected.²³

Antibiotic Stewardship

The problem of antibiotic-resistant bacteria is a real and growing one. The solution lies in the responsible use of antibiotics through quick, accurate diagnosis of infection and the timely termination of antibiotic therapy once it has achieved its purpose. In Europe, PCT is being used effectively to monitor antibiotic therapy (see Figure 3).
For patients requiring antibiotic therapy, determinations of the efficacy of an antibiotic being administered and decisions about whether to move to more aggressive treatment strategies are often based on parameters such as white blood cell count (WBC), blood cultures, and chest x-rays. Determining the correct approach may be challenging, since WBC may remain elevated due to pre-existing co-morbidities, blood cultures take 24-48 hours to mature, and changes to the level of chest infiltrates are often not apparent for several days. Such challenges may result in patients receiving non-efficacious antibiotics for a longer period of time, unnecessary switching to more aggressive antibiotics, or continuing antibiotics longer than necessary. This can increase treatment-related costs along with the risk of developing bacterial resistance to antimicrobial therapies.
Shorter antibiotic therapy is associated with reduced costs, particularly when broad-spectrum antibiotics are used.²⁴ Possible reductions in the length of ICU and hospital stays, as a consequence of appropriate antibiotic therapy, may have an even greater impact on treatment-related costs.²⁴
As a marker for sepsis severity, PCT provides useful information to help guide clinical decisions regarding antibiotic therapy. In a 2009 multicenter trial studying antibiotic therapy in LRTI infections, an algorithm with PCT cutoff ranges was not inferior to algorithm-based clinical guidelines in terms of adverse outcomes and was more effective in reducing antibiotic exposure and associated adverse effects. The mean duration of antibiotics exposure in the PCT-guided group versus the control groups was lower in all patients (5.7 versus 8.7 days; relative change: -34.5%).²⁵
In a 2007 randomized trial of PCT to guide antibiotic therapy, antibiotics were stopped when PCT levels had decreased by more than 90% from the initial value, but not before day three (if baseline PCT levels were less than 1µg/L) or day five (if baseline PCT levels were more than 1µg/L). In the control patients, clinicians based the duration of antibiotic therapy on empirical rules. PCT guidance resulted in a median four-day reduction in the duration of antibiotic therapy, an overall reduction in antibiotic exposure, and an ICU stay of two fewer days, without any adverse outcome.²⁴ These results were recently confirmed in a multiple center non-inferiority trial in France.
The concept of using PCT for antibiotic therapy decisions has been studied in 11 randomized controlled trials involving more than 3500 patients. All these trials showed a consistent reduction in antibiotic use without negatively affecting clinical outcomes.
PCT’s unique kinetics can also help in guiding changes in antibiotic therapy in patients with sepsis or other life-threatening systemic bacterial infections. PCT levels can monitor the course and prognosis of an infection, enabling clinicians to tailor the therapeutic interventions more efficiently.²⁶ This has been demonstrated in monitoring patients with sepsis, septic shock, VAP, and CAP.^24,27,28
In this manner, PCT helps enable the tailoring of antibiotic treatment to each patient’s individual clinical situation and physiological response to therapy. This serves to reduce significantly instances in which antibiotics are overused, thus reducing the risks posed by antibiotic-resistant bacteria.

Function and Future

PCT is already being used around the world to great effect in diagnosing sepsis and other life-threatening systemic infections. Seventy-one documented clinical trials involving PCT are currently ongoing, pointing to further uses for this valuable prohormone. Although PCT is currently approved in the United States for diagnosing only sepsis, it is only a matter of time before its full potential is realized. Even now, many leading physicians use PCT in the United States and abroad to diagnose infections ranging from hospital-acquired pneumonia to meningitis. Even though PCT is used routinely in Europe to monitor antibiotic therapies, it is currently not approved for that use in the United States. However, as the problem of antibiotic-resistant super bugs continues to escalate, regulators will surely see the value in implementing this versatile prohormone to promote antibiotic stewardship.

References

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Philipp Schuetz, MD, is a clinical researcher at Beth Israel Deaconess Medical Center (Boston). He can be reached via e-mail at pschuetz@hsph.harvard.edu.