July 2009: Volume 35, Number 7
Clinical Utility in Diagnosing Sepsis
By Kristopher A. McGee, MD and Nikola A. Baumann, PhD
Identifying patients with bacterial infection and sepsis is a major challenge in emergency departments and intensive care units. More than 750,000 Americans develop sepsis each year and mortality rates increase with severity of disease, approaching 60% in patients with septic shock. Furthermore, as many as 12% of infants presenting with fever to the emergency department have sepsis, a significant cause of morbidity and mortality. Cases of severe sepsis are expected to rise in the future for several reasons, including: increased awareness and sensitivity for the diagnosis; increasing numbers of immunocompromised patients; wider use of invasive procedures; more resistant microorganisms; and an aging population.
Since early diagnosis and treatment may prevent significant morbidity and mortality, there is great interest in identifying reliable sepsis markers to aid in diagnosis, guide therapy, and serve as prognostic markers. In the past decade, a large number of studies have been published evaluating procalcitonin (PCT) as a serum marker of systemic inflammation, infection, and sepsis. This article will focus on the clinical utility and limitations of serum PCT in diagnosis, guiding treatment, and monitoring sepsis and serious bacterial infections.
Overview of Sepsis
Systemic inflammatory response syndrome (SIRS) encompasses a variety of complex findings that result from systemic activation of the innate immune response. The clinical parameters include two or more the following: fever (>38? C) or hypothermia (<36? C), increased heart rate (>90 beats/min), tachypnea (>20 breaths/min) or hyperventilation (PaCO2 <32 mm Hg), and altered white blood cell count (>12,000 cells/mm3 or <4000 cells/mm3) or presence of >10% immature neutrophils. Sepsis is defined as SIRS resulting from infection, whether of bacterial, viral, fungal, or parasitic origin. Severe sepsis is associated with at least one acute organ dysfunction, hypoperfusion, or hypotension (1, 2).
The diagnosis of sepsis is difficult because clinical signs and symptoms are nonspecific and often overlap with other non-infectious causes of systemic inflammation; however, early diagnosis and treatment are critical for improving survival rates. Multiple approaches to treatment exist and the 2008 Surviving Sepsis Campaign guidelines developed by the European Society of Critical Care Medicine, the International Sepsis Forum, and the Society of Critical Care Medicine (SCCM) recommend initiating hemodynamic support and adjunctive therapy as soon as possible, including administration of broad spectrum antibiotics (3).
An ideal marker for diagnosing sepsis would be specific for systemic inflammation resulting from infection. Because most cases of sepsis are associated with bacterial or fungal infection, culture often is considered the gold standard for diagnosis of infection. However, culture lacks sensitivity and specificity. Nevertheless, current guidelines recommend culture for all patients suspected of having sepsis, with the caveat that >50% of cultures may be negative in patients who have severe sepsis or septic shock. In addition, there is a substantial time delay of at least 24 hours before culture results are available. This delay hinders clinicians’ ability to make informed treatment decisions in situations that require immediate action.
Traditional markers of systemic inflammation, such as CRP and white blood cell count (WBC), also have proven to be of limited utility in identifying ill patients who require antimicrobial therapy. The sensitivity and specificity of these measurements for bacterial infection are low.
These shortcomings in both culture and available blood tests have driven researchers to find other more sensitive and specific markers. In recent years, PCT has been the focus of much attention as a candidate marker for systemic inflammation, infection, and sepsis, both in children and adults.
A Procalcitonin Primer
PCT is a 116-amino acid polypeptide precursor to the calcium regulatory hormone calcitonin. It is composed of three sections: the amino terminus (N-ProCT), immature calcitonin, and katacalcin (Figure 1, below). Synthesis of PCT is regulated by the Calc-1 gene located on chromosome 11. In healthy individuals production of PCT and subsequently calcitonin is restricted to the thyroid C-cells (1, 2).
Calcitonin, and its precursor PCT, can increase in the serum of patients with neuroendocrine tumors, including medullary thyroid cancer, small cell lung cancer, and carcinoid tumors. Under these circumstances, PCT is cleaved post-translationally to form immature calcitonin that is then truncated to yield calcitonin, the only peptide known to have biological activity in humans (1, 2). It is important to note that PCT is present at very low concentrations (<0.05 ng/mL) and may be undetectable by some assays in healthy individuals.
In systemic inflammatory conditions, inflammatory mediators trigger ubiquitous production of procalcitonin by non-neuroendocrine cells throughout the body. These cells are stimulated to synthesize large amounts of PCT; however, they lack the capability to modify PCT post-translationally. Because of this, high concentrations of calcitonin are not observed in patients with systemic inflammation and sepsis. Induction of Calc-1 transcription and expression of calcitonin mRNA has been demonstrated in extra-thyroidal tissues, including liver, kidney, pancreas, adipose, and white blood cells. The stimulus for gene transcription and procalcitonin secretion appears to be both directly via microbial toxins and indirectly via inflammatory mediators, such as interleukin (IL)-1, IL-6 and tumor necrosis factor-α (TNF-α) (1, 2, 8).
Primary Structure 116-kD Precursor Polypeptide of Calcitonin
Procalcitonin is composed of three sections: the amino terminus (N-ProCT), immature calcitonin, and katacalcin
Role of PCT in the Inflammatory Response
Early in the evolution of the inflammatory response, cytokines such as TNF-α and IL-6 rise within the first 1 to 3 hours (1). However, these cytokines only remain elevated for up to 8 hours. Hyperprocalcitoninemia in systemic inflammation or infection occurs within 2 to 4 hours, often reaches peak concentrations in 8 to 24 hours, and persists for as long as the inflammatory process continues.
The half-life of PCT is approximately 24 hours; therefore, concentrations normalize fairly quickly with the patient’s recovery. In comparison, CRP takes 12 to 24 hours to rise and remains elevated for up to 3 to 7 days. Because PCT concentrations increase earlier and normalize more rapidly than CRP, PCT has the potential advantage of earlier disease diagnosis, as well as better monitoring of disease progression.
Researchers have not determined the exact role PCT plays in the pathogenesis of sepsis. In animal studies, administration of PCT to septic hamsters doubled the death rate, whereas administration of PCT antiserum increased survival. Interestingly, large quantities of PCT administered to healthy animals showed no noticeable deleterious effects or mortality, suggesting that PCT is only harmful in the context of other factors that accompany systemic inflammation and infection. Some evidence suggests that PCT modifies smooth muscle activity through intermediaries such as nitric oxide, thereby contributing to vascular modifications during sepsis (1, 2).
Lab Tests for PCT
Several quantitative PCT assays are available in the U.S., with additional assays, including a rapid, qualitative PCT available outside of the U.S. Though highly desirable, no assay detects the 116-kDa PCT peptide exclusively. All assays detect various portions of several calcitonin precursors, using a combination of monoclonal mouse anti-katacalcin antibodies and monoclonal or polyclonal sheep anti-calcitonin antibodies (1, 2).
FDA-cleared PCT assays include BRAHMS PCT LIA, BRAHMS PCT Kryptor, and bioMérieux’s VIDAS BRAHMS PCT assay. Both Roche and Siemens have assays in development for their automated platforms. The early PCT assays were batch assays based on manual immunochemistry methods (BRAHMS PCT LIA, formerly known as LUMItest PCT), with assay times of approximately 3 hours. PCT assays with shorter incubation times are now available on random access automated platforms (BRAHMS Liaison and Kryptor). The Kryptor assay, cleared by the FDA in March 2008, uses time-resolved, amplified-cryptate emission (TRACE) technology with an assay time in the 25 to 40 minute range.
The assay used in most studies has been the PCT LIA (LUMItest PCT). The limit of detection (mean +2 standard deviations) of this assay is reported as 0.08 ng/mL and the functional sensitivity (20% CV) is approximately 0.5 ng/mL (2). Therefore, values <0.5 ng/mL lack precision and are subject to error. Also, since 0.5 ng/mL exceeds the average PCT concentration in healthy individuals by more than ten-fold, any mild increase in PCT cannot be measured. The Kryptor and VIDAS assays, however, have manufacturer-reported functional sensitivities of 0.06 ng/mL and 0.09 ng/mL, respectively. These assays may able to quantitate mild elevations and detect relatively small day-to-day variations during a patient’s clinical course.
Elevated Serum PCT: Specificity and Limitations
Even though PCT is virtually undetectable in healthy individuals, elevated serum PCT concentrations are not specific for sepsis. Many studies have linked elevated PCT to SIRS, localized bacterial infection, autoimmune disease, burns, severe trauma, surgery, pancreatitis, as well as viral, parasitic, and fungal infections (1). Due to the vast range of conditions resulting in hyperprocalcitoninemia, emphasis has been placed on the degree of elevation rather than elevation itself.
Patients with the highest serum PCT levels typically have systemic bacterial infections or multi-organ failure commonly associated with severe trauma. PCT <0.5 ng/mL is considered normal, which was determined in many cases by functional sensitivity of early assays, whereas levels >10 ng/mL are considered significantly elevated. Serum concentrations between 2 to 10 ng/mL are considered suggestive of sepsis, whereas PCT concentrations between 0.5 to 2 ng/mL indicate the possibility of sepsis but do not rule out other causes of elevated PCT (1, 2). Figure 2 presents an algorithm for interpreting PCT levels in JCV patients with suspected sepsis. These cut-offs are merely guides, however, and there are reports of patients who have sepsis but whose serum concentrations are low. Therefore, clinicians must cautiously evaluate a patient’s PCT serum concentration in the context of a full clinical assessment.
Guide to Interpreting PCT Levels in ICU Patients
Measuring serum PCT in critically ill patients has value for evaluating risk of sepsis, but the results need be interpreted with caution, taking into account diverse clinical settings and limitations.
However, not every sick patient with elevated PCT has sepsis. As mentioned previously, elevations of PCT are seen in many clinical settings, including but not limited to inhalation injury, trauma, surgery, pancreatitis, heat stroke, and some cancers. Typically, PCT ranges between 2 to 3 ng/mL in these settings; however, the concentration in severe cases may climb as high as 10 to 20 ng/mL. Clearly, sound clinical judgment is necessary when evaluating an infection in these patients. A sustained elevation or marked increase of PCT may indicate the advent of infection or sepsis; therefore, serial measurements may be useful to identify trends in serum concentrations.
In studies of patients with severe infection, serum PCT concentrations vary widely. Studies have shown that increases of hundreds or even thousands-fold above baseline are associated with more severe bacterial infections. Conversely, many patients diagnosed with severe sepsis have been reported to have serum concentrations <2 ng/mL and some even <0.5 ng/mL. Most researchers, however, continue to define a threshold value for the diagnosis of sepsis of >2 ng/mL. Even though there are overlapping values, septic patients as a group have statistically higher serum PCT values. Furthermore, although there are exceptions, patients with extremely high serum PCT levels tend to be sicker and have a worse prognosis. The real challenge that remains is identifying sepsis in those patients with indeterminate serum concentrations in the 0.5 to 2 ng/mL range.
PCT’s Role in Sepsis Diagnosis
Several systematic reviews and meta-analyses have evaluated the utility of PCT, often by comparison to CRP, for diagnosing bacterial infections and differentiating sepsis from non-infectious causes of SIRS (4–6). Currently, the lack of a gold standard for the diagnosis of sepsis makes it difficult to assess the accuracy of the PCT marker. Both the definition of sepsis and the gold standard for diagnosis vary from study to study and contribute to discrepancies in the literature.
However, the majority of studies comparing diagnostic accuracy of CRP to PCT for diagnosis of sepsis or bacterial infection in hospitalized patients have shown serum PCT to be a superior marker. A meta-analysis evaluating these markers for diagnosis of bacterial infections showed that PCT had a sensitivity of 85% (95% CI, 76–91%) versus 78% (95% CI, 70–85%) for CRP. PCT was also more specific (83% (95% CI, 68–92%)) than CRP (60% (95% CI, 38–79%)) for differentiating bacterial from noninfectious causes of inflammation (4). Another report compared 15 studies and summary receiver operating characteristic curves (SROC) for the two markers and found PCT (Q* value 0.78) to be significantly better than CRP (Q* value 0.71) for diagnosing sepsis, severe sepsis, or septic shock in ICU patients following surgery or trauma (5). Based on the results, the researchers concluded that PCT should be included in diagnostic guidelines for sepsis and part of clinical practice in ICUs.
Another meta-analysis designed to assess the accuracy of PCT for sepsis diagnosis in critically ill patients concluded that PCT cannot be used to distinguish sepsis from SIRS in this patient population (6). Strict inclusion criteria for studies were applied including diagnosis of sepsis according to accepted definitions by the American College of Chest Physicians/SCCM Consensus Conference and confirmed presence of infection by microbial culture. The pooled diagnostic odds ratio (OR) of 7.79 (OR >100 high accuracy, 25 to 100 moderate accuracy, <25 not helpful) indicated that PCT results were unlikely to be helpful in assisting clinical decision making—starting antibiotics or ruling out sepsis—in this group of patients. Such results suggest that the diagnostic accuracy of PCT would likely be different depending on the population and setting.
Researchers have been keen to establish PCT as a marker for sepsis in the very young to avoid invasive diagnostic procedures and unnecessary treatment in this patient population. For the most part, the results have been variable. Recently, however, a study involving 234 infants and using the BRAHMS Kryptor assay with a cutoff value of 0.12 ng/mL, reported a sensitivity of 95.2%, specificity of 25.5%, and negative predictive value of 96.1% for identifying definite and possible bacterial infections in febrile infants presenting to the emergency department (7). While the specificity was low, the strength of the study is that all cases of bacteremia were identified. Additionally, using the lower cutoff, infants at low risk for serious bacterial infections could also be identified.
Guiding Antibiotic Therapy, Prognosis
It is well known that excessive use of antibiotics contributes to the spread of antibiotic-resistant microorganisms. Acute respiratory tract infections are the most common reason for antibiotic therapy in the primary care setting, despite the fact that such infections primarily have a viral etiology. PCT has been studied in this setting using more sensitive assays in order to better define those with bacterial infection. The general consensus is that PCT concentrations <0.1 ng/mL are highly suggestive of a non-bacterial etiology, whereas a value >0.25 ng/mL is suggestive of bacterial etiology (8). A recent study used these cutpoints to determine which patients should receive antibiotic therapy and found a significant reduction in antibiotic usage without compromising patient outcome (9). Compared with standard treatment, PCT-guided therapy was associated with a 72% lower rate of antibiotic prescriptions.
Daily measurement of PCT has also demonstrated utility in monitoring appropriateness of antimicrobial therapy and predicting outcome in patients with sepsis. Management in the early stages of sepsis is critical and often requires empirical antibiotic therapy. A recent study of ICU patients demonstrated that appropriate empirical antibiotic therapy was associated with a decline in PCT concentrations between day 2 and 3 following the onset of sepsis (10). Additionally, researchers found a ≥30% decrease in PCT levels between day 2 and 3 to be an independent predictor of survival. While these results are encouraging, further studies are required to fully validate the role of PCT in guiding therapy and prognosis.
A Future with Better Diagnosis
Sepsis is a complex clinical syndrome that exacts a huge burden on the healthcare system. While measuring serum PCT levels in sick patients during infection has value in diagnosing the condition, the results need be interpreted with caution, taking into account diverse clinical settings and limitations. Research also has demonstrated that changes in PCT levels have utility in monitoring treatment. The development of highly sensitive and specific assays probably will enhance our ability to detect minute PCT changes. This will help both in better identifying subtle trends during the course of illness—particularly worsening local infections—and monitoring response to therapy. For now, PCT is only one of many indicators for diagnosis and prognosis of sepsis and will likely remain a supplement to clinical data and other markers of inflammation until new more specific markers or assays become available.
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Kristopher A. McGee, MD, is a pathology resident in the department of pathology at the University of Illinois at Chicago.
Nikola A. Baumann, PhD, is director of clinical chemistry at the University of Illinois Medical Center and assistant professor in the department of pathology at the University of Illinois in Chicago, Ill.