Procalcitonin is an emerging biomarker in the diagnosis of severe bacterial infections and sepsis and is increasingly being used by clinicians to manage severely ill patients.
|Figure 1. Rising procalcitonin (PCT) values with severity of sepsis.6|
The incidence of sepsis is rapidly increasing, causing significant challenges for hospital critical care physicians who typically treat the condition. A common and frequently fatal condition, sepsis results from an inflammatory response to an infection. Infants, children, the elderly, and people with weak immune systems are particularly susceptible to sepsis. The infectious agent travels from the initial site infection to other organs via the bloodstream, which in severe cases can lead to organ failure, hypoperfusion, and hypotension. As a result, septic shock can occur, causing multiple organ dysfunction syndrome and death.
By definition, sepsis is characterized by a known or suspected source of infection plus two or more criteria of the systemic inflammatory response syndrome (SIRS) which are the following: fever, rapid pulse, respiratory depression, and abnormalities in the white blood cell count. However, these SIRS symptoms are very general and mimic other disorders, both viral and bacterial in nature. This presents many challenges for diagnosis and treatment. The ability to determine quickly and accurately if a condition is bacterial can lead to a more rapid diagnosis of sepsis infections, more appropriate treatment decisions, and efficient use of antibiotics.
Physicians often prescribe antibiotics to suspected sepsis patients as a precaution even before an infection is confirmed through testing. Laboratory tests can be time-consuming, and the longer a diagnosis takes, the more antibiotics and fluids are given to a patient to stop a presumed infection. However, administering antibiotics in conditions that mimic sepsis but do not actually have an infectious component can be deleterious. Moreover, some researchers believe that the imprecise use of antibiotics can worsen sepsis as certain antibiotics increase the breakdown of bacteria and the release of toxins into a patient’s bloodstream. Using unnecessary antibiotics can also damage a patient’s kidney, liver, or other organs.
Research has identified procalcitonin (PCT) testing as a rapid and dependable diagnostic approach for hospitals and physicians to identify and treat sepsis patients. This article discusses the advantages and efficiency of a PCT biomarker assay as a risk stratification tool, which allows physicians to detect rapidly the presence and severity of a bacterial infection, helping to reduce treatment-related costs and the unnecessary use of antibiotics.
PCT is produced in the thyroid as a peptide precursor of the hormone calcitonin. However, PCT is produced and secreted in a completely different manner from calcitonin. Normally, there is little to no procalcitonin circulating in the body. In response to mediators of a bacterial stimulus, PCT is produced and constitutively secreted from nearly every cell type in the body. In vira
|Figure 2: Cumulative effect of antimicrobial initiation following onset of septic shock-associated hypotension and survival.7|
l infections, this stimulus is lacking; therefore, PCT is not secreted in significant amounts. PCT appears to be blocked by viral mediators, which gives it a unique edge in identifying bacterial infections (see Figure 1). The procalcitonin molecule is an immune modulator with various specific putative biologic functions that distinguish it from other active inflammatory molecules.
The most interesting biologic function is that PCT is a particularly robust indicator of bacterially induced systemic inflammatory reactions. Since PCT levels are usually very low in the blood of healthy humans and systemic bacterial infections cause the protein to be produced by almost every organ in the body, an infection produces a rapid rise of PCT levels in the blood. This rapid rise of PCT levels can be detectable as early as three hours after the onset of a bacterial infection and can reach maximum values after 6-12 hours. This allows for the rapid identification of bacterial infections in a way that no other IVD test has previously allowed.
The severity of a bacterial infection can also be determined by assessing the PCT levels in the blood. Slightly elevated concentrations (<0.5 ng/ml) appear in cases of minor systemic inflammatory response, and intermediate values (0.5.-2.0 ng/ml) in significant but still moderate inflammatory reactions. These levels can often represent a localized infection. During severe systemic inflammatory reactions that are most likely due to sepsis, PCT levels will range between 2 and 10 ng/ml, and will reach very high values in cases of severe sepsis and septic shock (>10 ng/ml; see Figure 2). This dynamic analyte range makes PCT an effective tool for helping physicians assess the risk of sepsis and severe bacterial infection. Evaluating which patients are at high risk for developing severe sepsis or septic shock by measuring PCT can also aid physicians in deciding on patient management strategies, thereby improving outcomes.
A study of inflammatory markers, in which the accuracy of sepsis diagnosis was based on clinical models with and without PCT, found that 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—97% sensitivity and 78% specificity—to differentiate between patients with SIRS and those with sepsis-related conditions. The study concluded that adding PCT to a model based solely on standard indicators made a significant improvement on the ability to detect sepsis (likelihood ratio test; p=0.001), increasing the area under the receiver operating characteristic curves value for the routine-based model from 0.77 to 0.94.1 This indicates that while physicians without PCT measurements may be able to diagnose sepsis, a physician aided with PCT measurements is able to do a better job.
This study also found that PCT is useful in assessing the severity of sepsis. High PCT levels were associated with poor patient prognosis, and a rapid decrease of PCT levels during the first week after ICU admission signified a positive prognosis.1 A slow decrease or no decrease in PCT levels 48 hours after admission was consistently associated with a poor outcome. Virtually all patients in the study who died of sepsis or related complications had PCT levels that never fell below 1.1 ng/ml.1
PCT Biomarker Testing
Adding a PCT biomarker assay as a risk stratification tool for hospitals and physicians can help in identifying and treating severe systemic bacterial infections in patients. Quantitative diagnostic PCT biomarker assays can help to detect the production of PCT from the body’s organ systems in cases of systemic bacterial infection.
Clinicians using a PCT assay can identify patients who are at risk of severe sepsis. For example, the B·R·A·H·M·S PCT assay by Thermo Fisher Scientific enables clinicians to measure PCT levels in patients, allowing for appropriate clinical actions to be taken, with high levels indicating severe sepsis and low levels indicating minor systemic inflammatory response. This allows for quicker and better decisions to be made and ultimately more effective treatments. Unlike traditional infection diagnostic tools such as blood cultures, a PCT test can be done rapidly, with results often available to treating physicians within an hour. PCT testing has been a key element in infectious disease management in much of Europe for more than a decade. Recently, its use and applications have been increasing worldwide.
One reason for PCT’s growing popularity is that it has helped physicians in their risk assessments. If certain conditions can be excluded, others can be more readily identified, leading to more effective treatments. Healthcare professionals can make faster and better triage decisions, including therapeutic strategies as well as more targeted decision-making about hospital and intensive care unit admissions.
As with any other IVD test, understanding the kinetics and limitations of PCT testing is important. There are a few situations in which PCT levels may be low in the presence of an infection (e.g., very localized infections such as an abscess or the earliest hours of a systemic infection). Similarly, there are cases in which PCT levels may be high in the absence of serious bacterial infections (e.g., C cell carcinoma of the thyroid). As with any IVD test, it is important to keep the test’s performance parameters in mind and use the test within the context of overall clinical decision-making.
PCT Biomarker Testing in the ICU
Sepsis presents complex challenges in an ICU setting, and traditional methods of dealing with bacterial infections have many disadvantages that can negatively affect a patient’s health and increase ICU treatment-related costs. Providing hospital care for patients with sepsis is costly, according to a study that found annual U.S. hospital costs associated with septic patient care totaled $16.7 billion.2 Patients with sepsis typically have longer ICU stays than non-sepsis ICU patients. Moreover, the total length of hospital stays is longer for sepsis patients than patients with other medical conditions.
Traditionally, patients with SIRS symptoms are given antibiotic therapy before sepsis is confirmed through testing. This is based on the knowledge that the critical determinant of a patient’s survival from septic shock is the early administration of antibiotic therapy: the sooner patients receive antibiotics after the onset of sepsis-related hypotension, the more likely they are to survive (see Figure 3). Such testing as white blood cell count (WBC), blood cultures, and chest x-rays are used to establish the effectiveness of the antibiotic being administered.
|Figure 3: Receiver operating characteristic curve (ROC) of PCT improving the accuracy of clinical diagnosis.1 (Reprinted with permission of the American Thoracic Society.)|
However, these tests are not always time efficient or reliable when dealing with bacterial infections. For example, it can take days for definitive blood culture results to become available; leukocyte counts and differentials can be influenced by non-infectious disorders and are known to be influenced by many common medications, which reduce their utility. This not only results in the patient receiving unnecessary and ineffective treatments but can also increase the risk of developing resistance to those antibiotic therapies that are incorrectly prescribed.
ICU physicians can use PCT testing to determine the severity of a patient’s condition less than an hour after a blood sample is taken. For critical-care physicians, timing is critical when treating severe bacterial infections as the progression of the illness is directly affected by when patients receive appropriate treatments. Research has shown that early diagnosis and treatment result in positive outcomes for patients. By monitoring PCT levels, physicians can make risk assessments earlier and treat patients sooner.
PCT biomarker testing allows physicians to identify the presence or absence of bacterial infections at an early stage and prescribe the appropriate treatments to patients. This is demonstrated in a 2010 study on using PCT to predict bacteremia in patients with community acquired pneumonia (CAP). Current guidelines recommend blood culture sampling from hospitalized patients with suspected CAP. However, this method can cause patient harm through unnecessary phlebotomies, increase treatment costs, and cause medical errors (blood cultures are subject to both false positive and false negative results with potential mistreatment ramifications).
In this subset of the proHOSP study, both PCT levels and blood cultures were taken from patients with CAP. The results showed that PCT levels accurately predicted blood cultures positivity in patients, demonstrating the potential of PCT to predict bacteremia and reduce the number of blood cultures drawn in the ICU.3 Using PCT in targeting rational blood culture utilization allows for more direct allocation of limited healthcare resources while maintaining patient safety.
Treatment-related costs such as ICU stay and hospital stay are also reduced as a result of administering appropriate treatments. Researchers have found that PCT testing can reduce the economic costs associated with sepsis. In a 2004 study of patients with suspected lower respiratory tract infections, patients with PCT values of less than 0.25 were considered non-indicative of a bacterial infection, and antibiotic use was discouraged. Patients with PCT levels between 0.25 and 0.5 μg/L were considered indicative of a possible bacterial infection, and the treating doctor was advised to initiate antibiotic treatment. For PCT values of 0.5 μg/L or greater, antibiotic treatment was strongly advised. The study concluded that PCT testing substantially and safely reduced antibiotic overuse in the patients studied and antibiotic exposure by 50%, equating to 39 fewer antibiotic courses per 100 patients. Significantly, the study found that withholding antibiotic treatment was safe and did not compromise outcomes.4
In a 2007 randomized trial of PCT for guiding antibiotic therapy, antibiotics were stopped when PCT levels decreased by approximately 90% from the initial value, but not before day three (if baseline PCT levels were <1 μg/L) or day five (if baseline PCT levels were ≥1 μg/L). This was in contrast to the control patient treatment group in which clinicians based the duration of antibiotic therapy on empirical rules (standard practice unaided by these PCT guidelines). The 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 days less without any apparent patient harm. These results indicate that using PCT testing to identify sepsis and help guide antibiotic therapy in septic patients can reduce unnecessary use of antibiotics and shorten the duration of treatment. The study authors pointed out that the judicious use of PCT testing to guide therapy had a positive effect on costs by reducing costly antibiotic doses and an impact on treatment-related costs from reductions in the lengths of hospital and ICU stays.5
Sepsis continues to be a considerable problem in hospitals and ICUs, presenting significant challenges to physicians due to time-consuming diagnostic methods and the lack of specific clinical symptoms and indicators. This can lead to suboptimal treatment decisions, high treatment-related costs, and increased morbidity and mortality.
Studies presented throughout this article found that PCT is a reliable biomarker of sepsis and bacterial infections. The PCT biomarker assay has proven to be a rapid and dependable alternative diagnostic and risk assessment tool to traditional methods such as blood cultures. ICU physicians can use the test to detect quickly the presence and the level of severity of infection and provide the most efficient and effective treatment, helping to minimize risk of progression to severe sepsis and unnecessary use of antibiotics.
In conjunction with other laboratory findings, the PCT biomarker test helps to reduce not only health risks in critically ill patients but also the treatment-related costs of sepsis. The length of ICU stays and inappropriate antibiotic treatments can be significantly reduced with rapid diagnosis, ultimately resulting in a decline in hospital costs. In the United States, FDA cleared the PCT biomarker assay in April 2008. According to FDA, PCT testing is intended for use in conjunction with other laboratory findings and clinical assessments to aid in the stratification of patients on the first day of ICU admission for progression to severe sepsis and septic shock.
The adoption of PCT testing has not been as robust in the United States as it has been in Europe. In most of Europe, PCT testing is available on a variety of common laboratory platforms. However, due to regulatory delays in the United States, many of these IVD commercial platforms do not yet have PCT testing on their North American test menus. In these days of tight laboratory budgets, lab directors have been waiting until this test is made available for their lab equipment in their institutions. It is important to note that at the systems level, this wait incurs substantial costs for both hospitals (in terms of unnecessary admissions, delayed discharges, inappropriate level of care assignments) and patients (in terms of prolonged hospital stays, loss of quality of life, and unnecessary antibiotic exposure).
Through the use of PCT testing, physicians have the ability to identify quickly sepsis in ICU patients and prioritize those who are at most risk of progressing to severe sepsis. This ensures efficient and effective treatments for patients and could potentially reduce the current high fatality rates caused by sepsis.
1. S Harbarth, et al., “Diagnostic Value of Procalcitonin, Interleukin-6, and Interleukin-8 in Critically Ill Patients Admitted with Suspected Sepsis,” American Journal of Respiratory and Critical Care Medicine 164 (2001): 396-402.
2. Angus, et al., “Epidemiology of Severe Sepsis in the United States: Analysis of Incidence, Outcome, and Associated Costs of Care,” Critical Care Medicine 29, no. 4 (2001).
3. Muller, et al., “Procalcitonin Levels Predict Bacteremia in Patients with Community-Acquired Pneumonia: a Prospective Cohort Trial,” Chest (2010).
4. Christ-Crain, et al., “Effect of Procalcitonin-Guided Treatment on Antibiotic Use and Outcome in Lower Respiratory Tract Infections: Cluster-Randomised, Single-Blinded Intervention Trial,” Lancet 363, no. 9409 (2004): 600-607.
5. Schuetz, et al., “Effect of Procalcitonin-Based Guidelines vs Standard Guidelines on Antibiotic Use in Lower Respiratory Tract Infections: the ProHOSP Randomized Controlled Trial,” Journal of the American Medical Association 302, no. 10 (2009): 1059–1066.
6. M Meisner, “Procalcitonin: Biochemistry and Clinical Diagnosis,” Uni-Med Science, 2010.
7. A Kumar, et al., “Duration of Hypotension Before Initiation of Effective Antimicrobial Therapy is the Critical Determinant of Survival in Human Septic Shock,” Critical Care Medicine 34, no. 6: 1589-1596.
Sean-Xavier Neath, MD, PhD is assistant clinical professor of medicine in the Department of Emergency Medicine at the University of California, San Diego. He can be reached at firstname.lastname@example.org.