Elsevier

International Journal of Cardiology

Volume 223, 15 November 2016, Pages 390-397
International Journal of Cardiology

Procalcitonin: A new biomarker for the cardiologist

https://doi.org/10.1016/j.ijcard.2016.08.204Get rights and content

Highlights

  • The inflammatory blood marker procalcitonin (PCT) aids in the diagnosis of bacterial infection and appropriate antibiotic use

  • The potential benefits of PCT testing in patients with acute cardiovascular disorders are being actively investigated

  • PCT provides information on the likelihood of an infectious cause in patients presenting with acute cardiovascular symptoms

  • PCT also provides prognostic information and correlates with clinical outcomes in different cardiovascular disorders

  • Prospective interventional trials may highlight the utility of PCT as a biomarker in managing acute cardiovascular disorders

Abstract

Due to its high accuracy for the diagnosis of bacterial infections, the inflammatory biomarker procalcitonin (PCT) is increasingly being used in patients with suspected infection. In patients with infections of the respiratory tract, it allows rapid rule out of bacterial etiology and facilitates decisions pertaining to antibiotic management. A growing body of evidence also supports PCT testing in patients with cardiovascular disorders including, but not limited to, those with shortness of breath, possible heart failure, suspected endocarditis, and acute coronary syndromes. In these clinical situations, PCT may provide diagnostic information on the likelihood of an infectious cause in cardiovascular patients presenting with acute symptoms such as dyspnea. It may also have a prognostic value that correlates with clinical outcome and can potentially guide drug therapy. This narrative review summarizes current concepts and evidence from the published literature on the strengths and limitations of PCT as a biomarker, with a focus on patients with a variety of cardiovascular disorders.

Introduction

Patients with cardiovascular disease often present to emergency care with nonspecific symptoms including chest tightness, chest pain, shortness of breath, cough, sweating, and anxiety [1]. While these symptoms may be related to a number of possible acute cardiovascular events such as acute coronary syndrome or acute heart failure, other causes need timely rule out in order to provide appropriate treatment. Infections of the respiratory system frequently cause similar symptoms and may mimic acute cardiovascular disease [2]. Thus, for the cardiologist assessing patients with the above-mentioned symptoms in the emergency care setting, accurate and timely rule out of bacterial infections remains a priority and—in light of the heterogeneity of pathogens, varying severity, and differences in patient populations—an everyday clinical challenge.

Reliable clinical or microbiological parameters to establish or refute the diagnosis of a bacterial infection of the respiratory system have largely been lacking [3]. Current microbiological methods are still plagued by significant delays and low sensitivity (e.g., blood culture) or low specificity due to possible contamination and colonization (e.g., sputum cultures) [4], [5]. Unlike troponin for diagnosis of myocardial infarction, more traditional markers of inflammation—such as erythrocyte sedimentation rate (ESR), white blood cell (WBC) counts, and C-reactive protein (CRP)—lack specificity for bacterial infections and typically increase as part of the systemic acute phase response that is also seen in patients with non-infectious illnesses such as cardiovascular diseases [4], [6]. This being the case, the inflammatory blood marker procalcitonin (PCT) has stimulated great interest as a more specific blood biomarker for bacterial infections [7], [8].

Procalcitonin is released ubiquitously in response to endotoxin and other mediators secreted during bacterial infections (e.g., interleukin-[IL]-1β, tumor necrosis factor [TNF]-α, and IL-6) [9]. Its levels thus strongly correlate with the extent and severity of bacterial infections [10]. Upregulation of PCT expression is attenuated by interferon-gamma (INF-γ), a cytokine released during viral infections [11]. These characteristics make PCT more specific for bacterial infections than markers such as WBC or CRP, and may allow PCT to be used in differentiating bacterial from viral infections and other non-infectious illnesses [12], [13], [14]. Procalcitonin shows a favorable kinetic profile that makes it well suited for use as a clinical marker: circulating levels increase promptly (within 6–12 h) upon stimulation and halve daily when the bacterial infection is controlled by the host immune system or through antibiotic therapy. Moreover, its levels correlate with bacterial load [15], [16], [17] and severity of infection [6], [18], [19], [20]. Procalcitonin concentration thus has prognostic implications and its kinetics predict clinical outcomes in patients with community-acquired pneumonia (CAP) [19], [21], [22], [23] and in critically ill patients with sepsis [24].

For the above reasons, PCT has been extensively evaluated as a diagnostic marker for infections and as a tool for improved decision-making in antibiotic stewardship programs. A 2007 meta-analysis that included 17 observational studies totaling over 2000 patients found a high discriminatory value of PCT for bacteremia (area under the curve [AUC] 0.84, pooled sensitivity 0.77, 95% confidence interval [CI] 0.72–0.81, pooled specificity 0.79, 95% CI 0.74–0.84), with positive blood cultures serving as the gold standard [17], [25]. However, these were all critically ill patients with clinical signs of a systemic inflammatory response syndrome (SIRS) and possible infection. Additionally, several randomized controlled studies have investigated the use of PCT to assist in decisions pertaining to the initiation and duration of antibiotic therapy, or both (“antibiotic stewardship”), particularly in patients with respiratory tract infections. These trials used similar clinical protocols with recommendations for or against antibiotic treatment based on four different PCT cut-offs adapted to patients' clinical risk profiles [26], [27]. Initial antibiotics were withheld if PCT remained low (i.e., < 0.25 ng/mL or < 0.1 ng/mL) in patients with low risk for systemic infection (e.g., patients with respiratory symptoms and lack of an infiltrate on chest X-ray, suggestive of acute bronchitis or chronic obstructive pulmonary disease [COPD] exacerbation) [27]. For sepsis patients in the critical care setting, a PCT < 0.5 ng/mL is usually considered to be low, arguing against bacterial infection and thus need for antibiotic therapy, because patients with severe sepsis or shock usually have much higher levels (i.e., > 2.0 ng/mL) [27]. If PCT values were higher and antibiotic therapy was initiated, repeated PCT measurements every 1–2 days, depending on the clinical severity of disease, were recommended. Discontinuation of antibiotics was recommended using the same cut-off ranges or, if initial levels were especially high, when a marked (i.e., 80%–90%) drop in PCT levels was observed. For high-risk patients in critical care due to presumed bacterial infections, protocols focused on antibiotic therapy discontinuation if a patient showed a clinical recovery and PCT levels decreased to “normal” levels (≤ 0.5 μg/L), or by at least 80–90% of its peak value [28]. In these patients, PCT-guided therapy facilitated reductions in the duration of therapy and defined daily antibiotic doses, with these reductions being associated with an appreciable decrease in mortality. Of note, outside respiratory infection and sepsis (e.g., stroke), other cut-offs have been proposed in the literature, mainly based on “optimal cut-offs” found in observational studies.

These protocols proved to be safe and highly effective in lowering antibiotic exposure. In fact, for low-severity patients, such as those with bronchitis and upper respiratory tract infections, reductions in antibiotic prescription rates by 60–70% were documented [27], [29], [30]. In higher-severity patients, PCT guidance resulted in a relative reduction in the duration of antibiotic treatment by 40% in patients with pneumonia and by 25% in the critical care setting. Not surprisingly, lower antibiotic exposure resulted in appreciable decreases in the incidence of antibiotic side effects and reduction in costs [31].

Besides respiratory infections and other infectious diseases, multiple recent studies have investigated the possible benefits of PCT testing in patients with cardiovascular disorders, including shortness of breath and possible heart failure, suspected endocarditis, cardiac arrest, and acute coronary syndromes, among others. In patients with shortness of breath, observational studies as well as a secondary analysis of a randomized trial found initial PCT levels to have a high prognostic value [32], [33]. These investigators reported worse clinical outcomes in patients treated with antibiotics over diuretics and nitrates despite their having low PCT levels that strongly suggested the absence of bacterial infection. In patients with endocarditis as well, PCT appears to have prognostic implications, with low levels helping to rule out the condition, especially its acute forms. Procalcitonin has also been shown to improve prognostic assessment in patients with acute coronary syndrome. However, a comprehensive review of studies on the utility of PCT in the management of a variety of cardiovascular disorders is not currently available. The aim of this narrative review is to present cardiologists caring for patients with cardiovascular disorders in the acute care setting with an overview of the published primary literature in this area. We focused on studies known to the authors to have influenced the field but did not perform a formal systematic search. Ongoing studies were included based on the awareness of the authors. We summarized the most important studies pertaining to this topic in Table 1 and discuss the studies according to clinical syndrome in the text.

In patients with a history of congestive heart failure presenting with acute respiratory symptoms such as cough, sputum production, shortness of breath, tachypnea, or pleuritic pain, differentiating acute heart failure from lower respiratory infection is challenging due to the overlapping clinical picture and radiological findings [34]. However, rapid and accurate differential diagnosis is of utmost importance. Delayed targeted therapy [35] or inadequate therapy [32] increases the risk of adverse patient outcomes. Lower respiratory infection can be found in a significant proportion of patients presenting to hospital emergency care with worsening congestive heart failure. In a large population-based study of more than 48,000 patients [36], lower respiratory infection was prevalent in 15% of patients with congestive heart failure. Importantly, this study also found infection to significantly increase mortality, with an odds ratio of 1.60 (95% CI, 1.38–1.85, p < 0.001) for in-hospital death. This increase in adverse patient outcomes may be attributable to the underlying infection per se. If the diagnosis of respiratory infection is delayed or missed, lack of inadequate antibiotic treatment and fluid resuscitation may directly contribute to adverse outcomes. Conversely, treating patients with acute heart failure with antibiotics and fluids in the absence of infection may worsen their prognosis.

A large study that included 4698 patients with congestive heart failure found PCT to be about 4-fold higher in heart failure patients when respiratory infection was present [37]. Similar results were also observed in the multinational Biomarkers in Acute Heart Failure (BACH) trial [32]. This study included 1641 patients presenting to the Emergency Department with shortness of breath, and documented significantly higher adjusted 90-day mortality rates in patients with a primary diagnosis of acute heart failure if no antibiotics were given despite a PCT elevation that suggested concomitant respiratory infection. Conversely, patients with a low PCT level [38] who were put on antibiotics also had higher 90-day all-cause mortality rates compared to their untreated counterparts. Although BACH was an observational study, which does not allow inference of causality, these results suggest that inadequate therapy, including inappropriate use or inappropriate withholding of antibiotics, may negatively affect mortality in acute heart failure patients.

These observations were confirmed in a secondary analysis of the randomized-controlled, antibiotic stewardship trial “ProHOSP” [39]. This analysis focused on patients with a prior medical history of congestive heart failure who presented to the Emergency Department with possible respiratory infection and were later randomized to a PCT-guided antibiotic management arm or a control arm. In the interventional arm, antibiotics were discouraged in patients with low PCT levels suggesting the absence of systemic bacterial infection and stopped early if PCT declined to normal values, suggesting cure of infection. In patients with low initial PCT levels (< 0.25 μg/L), the risk of adverse clinical outcome was significantly reduced in patients randomized to the PCT guidance arm (absolute difference − 16.0% [95% CI, − 28.4% to − 3.6%]). Antibiotic exposure was also significantly reduced (mean 3.7 ± 4.0 vs 6.5 ± 4.4 days, difference − 2.8 [95% CI, − 4.4 to − 1.2]) in this arm of the trial. Thus, use of PCT to guide the decision for or against initiation of antibiotic therapy in patients with a history of congestive heart failure and respiratory symptoms suggestive of respiratory infection resulted both in decreased antibiotic exposure and improved clinical outcomes. These data provide further evidence of the potential harmful effects of antibiotics when used indiscriminately in clinically symptomatic congestive heart failure patients without an underlying infection.

A recent pooled analysis of patients from two prospective cohorts of individuals presenting to the Emergency Department with shortness of breath revealed PCT as being able to facilitate the diagnosis and exclusion of pneumonia [40]. Levels of PCT were higher in patients with pneumonia (0.38 ng/mL vs 0.06 ng/mL, p < 0.001) and the AUC for PCT-based diagnosis of pneumonia was 0.84 (95% CI 0.77–0.91, p < 0.001). In patients in whom there was uncertainty between the diagnosis of heart failure and pneumonia, PCT levels facilitated the diagnosis and exclusion of pneumonia. Again, the data suggest that a low PCT level of < 0.1 ng/mL may help to rule out pneumonia, while increase levels to > 0.25 (or > 0.4) ng/mL may help to rule in an infection of the respiratory tract. Moreover, elevated PCT levels predicted 1-year mortality in patients with pneumonia (hazard ratio 1.8, 95% CI 1.4–2.3, p < 0.001) and showed additive value when elevated in conjunction with natriuretic peptides.

Based on these study data and previous trials in respiratory infection patients [26], [29], [39], the interpretation of PCT in CHF patients with respiratory symptoms and possible respiratory infection maybe as follows (Fig. 1): an initial low (< 0.25 ng/mL) or very low (< 0.1 ng/mL) PCT level points to absence of respiratory infection and no antibiotics should be used except in cases of high clinical suspicion or clinical instability. In such cases a re-testing of PCT after 6–24 h should be done. If PCT is increased (≥ 0.25 ng/mL), infection becomes more likely and an assessment of patient regarding respiratory infection is recommended followed by empirical antibiotic therapy. In such a case the monitoring of PCT every 2 days may allow early termination of treatment once PCT levels have come back to normal or dropped by at least 80% from the peak level.

A large, prospective, randomized-controlled trial again evaluating the use of PCT in patients presenting to the Emergency Department with shortness of breath and (suspected) heart failure (Improve Management of Heart Failure With Procalcitonin [IMPACT-EU], NCT02392689) is currently ongoing. This trial aims to recruit 792 patients and compare PCT-guided care with routine care in patients who present to the emergency department (ED) with the leading symptom being dyspnea. The study is planned to be completed by the end of 2016 and results are expected to shed additional light on the utility of PCT in this patient population.

Just as in patients with acute heart failure and respiratory infection, infection of the respiratory system also worsens prognosis in patients with stroke [41]. A meta-analysis that included four randomized trials found the risk of infection in patients with acute stroke to be reduced when preventive antibiotics were used, with a pooled odds ratio for infection of 0.44 (95% CI 0.23–0.86) [42]. Although mortality was lower in patients receiving antibiotic treatment, this finding did not reach statistical significance (pooled odds ratio for mortality 0.63, 95% CI 0.22–1.78). In addition, PCT has been found to be an independent predictor of respiratory infection in stroke patients. In one study involving 96 stroke patients who had been recruited prospectively, the odds ratio for infection was 51.2 if PCT was higher than 0.07 ng/mL [41]. Based on this finding and observational studies reporting higher PCT levels in stroke patients with infection, the STRAWINSKI trial (STRoke Adverse outcome is associated WIth NoSocomial Infections) seeks to assesses whether PCT-based early identification and treatment of respiratory infection improves functional outcomes after severe ischemic stroke [43]. The trial has been completed but results have not been published so far.

In addition to facilitating early diagnosis of infection, multiple studies have found PCT to have prognostic implications in stroke patients [44], [45]. One study that included 376 patients with acute ischemic stroke reported that, after adjustment for age, National Institutes of Health Stroke Score (NIHSS), and other vascular risk factors, PCT was an independent prognostic marker of 1-year functional outcome (odds ratio 2.33, 95% CI 1.33–3.44) and death (odds ratio 3.11, 95% CI 2.02–4.43) [45]. Moreover, PCT improved the AUC of the NIHSS score for functional outcome (from 0.74 to 0.85) and mortality (from 0.77–0.94).

Infective endocarditis is a life-threatening disease caused by infection of the endocardial surface of the heart, usually involving the heart valves, mural endocardium, or a septal defect [46]. Infective endocarditis continues to pose a diagnostic challenge for clinicians because of the various clinical presentations. This is mirrored in the current definition (i.e., modified Duke's criteria) that integrates clinical findings, microbiological study results, and imaging findings. These criteria over- and under-diagnose infective endocarditis, particularly in patients with subacute disease and atypical presentations [46]. In light of the expected benefits of early antibiotic treatment in patients with infective endocarditis, a sensitive marker for this condition would be highly desirable and may potentially improve outcomes.

Importantly, multiple studies have observed PCT to be highly associated with bacteremia—the main diagnostic criteria for endocarditis—in Emergency Department patients with fever [47], [48], [49]. In one observational cohort study that included 1083 patients with suspected infection, PCT was strongly associated with positive blood cultures (AUC 0.803) independent of the type of bacteria or the site of infection [49]. A low PCT cut-off of 0.1 ng/mL had a negative predictive value of 99.6% to rule out bacteremia. Thus, PCT is a promising marker for the evaluation patients with possible endocarditis.

Multiple studies have found PCT to be valuable in patients with infective endocarditis. A prospective cohort study including 67 consecutive patients admitted to the hospital with suspicion of endocarditis and 21 patients with infection confirmed by an interdisciplinary team that included an infectious disease specialist and a cardiologist who applied the Duke criteria found a strong association between PCT levels and endocarditis [50]. Procalcitonin levels were significantly higher in endocarditis patients (median 6.56 ng/mL vs 0.44 ng/mL, p < 0.001), with an AUC of 0.856 (95% CI 0.750–0.962). Procalcitonin also outperformed CRP in this study. The optimal PCT cut-off was 2.3 ng/mL, with a sensitivity of 81%, a specificity of 85%, negative predictive value of 92%, and a positive predictive value of 72%. Other studies have also evaluated PCT in patients with endocarditis. A recent meta-analysis that reviewed six studies including > 1000 episodes of suspected infection—of which roughly 20% were cases of confirmed infective endocarditis—revealed a slightly lower discriminatory value of PCT (AUC 0.71) [51]. Importantly, it suggested that a low PCT threshold should be used for ruling out endocarditis in routine clinical practice in lieu of an “optimal” cut-off. In line with this notion, the largest study to date evaluated PCT in 759 patients with suspected endocarditis and found a 97% negative predictive value if a very low PCT cut-off of 0.02 ng/mL was used [52].

Interestingly, there is growing evidence linking PCT to the extent of atherosclerosis and prognosis in patients with coronary artery disease. It is well known that inflammation plays a role in the pathophysiology of atherosclerosis. Additional inflammatory markers are also known to be elevated in patients with acute myocardial infarction, with CRP having been shown to predict the risk of recurrent events [53]. Levels of PCT have been shown in multiple studies to be elevated in patients with acute coronary syndromes, particularly in complicated cases [54, 55]. In one study, PCT levels were measured in 54 patients with acute coronary syndrome and found to be elevated in patients only if associated with severe left heart failure or resuscitation after cardiac arrest, or in the presence of bacterial infections [54]. Another study evaluating 2131 patients with coronary artery disease (CAD) with a follow-up of 3.6 years found PCT to have a strong prognostic value [55]. Patients who died of cardiovascular causes had significantly higher PCT concentrations, as did patients with acute coronary syndromes compared to patients with stable angina. In a Cox regression analysis, elevated PCT concentrations were related to cardiovascular mortality (hazard ratio 1.34, 95% CI 1.08–1.65, p = 0.007). However, despite these positive findings, the clinical benefit of PCT testing for diagnosis or prognosis in patients with CAD remains unclear today. Further studies investigating whether PCT provides information beyond that provided by established risk markers are needed.

In patients resuscitated from cardiac arrest, the initial whole-body ischemic insult followed by reperfusion are associated with a “sepsis-like” early, acute “post-cardiac arrest syndrome” [56], [57]. This syndrome is likely due to massive intestinal bacterial translocation and includes the non-specific, cascading release and activation of circulating cytokines, other immunological mediators, and pro-coagulatory factors, resulting in severe systemic inflammation. A growing consensus holds that the post-cardiac arrest syndrome may influence post-resuscitation outcomes following cardiac arrest [56]. Therefore PCT, as an easily and frequently measured inflammatory marker, has attracted interest as a potential prognostic factor in this setting. This interest has been heightened because cardiac arrest patients are typically subjected to mild therapeutic hypothermia, and the sedatives and muscle relaxants administered as part of this intervention confound patients' clinical assessment [58], [59]. Further, although many of these patients develop respiratory tract infections such as pneumonia or are even affected by sepsis, the therapeutic hypothermia attenuates signs and symptoms of infection such as fever.

Given the well-established role of PCT in patients with respiratory infections [27], [30], [60], [61], this analyte has also been studied for its utility in the early diagnosis/prediction of infectious complications in the post-cardiac arrest setting. Since 2003, at least 11 studies, conducted in 7 European countries or Japan, have examined the role of PCT in patients resuscitated from cardiac arrest [56], [57], [58], [62], [63], [64], [65], [66], [67], [68]. These observational studies have been conducted at single centers, with seven of the cohorts numbering 54 or less patients and the largest sample numbering 169 patients. All but one study [64] involved adults and only a minority of studies [58], [64], [68] were reported to include in-hospital as well as out-of-hospital cardiac arrest patients. However, the studies appeared to include patients with all types of initial heart rhythms.

Collectively, the reports on PCT use following resuscitation from cardiac arrest seem to have five main findings. First, levels of this biomarker appear to rise rapidly after cardiac arrest [68]. Second, PCT appears to be significantly associated with neurological outcome at 14 days [65], 3 months [56], and 6 months [58], [66], [68] and with in-hospital survival [64] at 3 months [56] or after an unreported interval [69], although a small study by two of the present authors casts doubt on the link between PCT levels and in-hospital survival [67]. Unfavorable outcomes were associated with higher absolute or peak PCT levels or sharper and more protracted PCT increases [67]. Third, there has been some suggestion that PCT may be a superior prognostic marker in the post-cardiac arrest resuscitation setting than are CRP [63], [64], [65], soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) [63], glial fibrillary acidic protein (GFAP) [66], or IL-6 [65]. However, statistical comparisons of these analytes generally were not published, and a recent study suggested that IL-6 was more closely linked to post-cardiac arrest syndrome (PCAS) severity than was PCT [57]. Fourth, in this setting of massive PCT expression triggered by generalized ischemia and reperfusion, this biomarker appears to lack the ability to facilitate the early identification of patients with infection [56], [63], [67], [68] or specifically, pneumonia or sepsis [58]. Finally, therapeutic hypothermia seems not to affect the nature of the PCT response to cardiac arrest, although it may decrease the magnitude of the response [65]; there appears to be no difference in the effects of hypothermia on PCT concentrations at 33 vs 36 °C [57].

These essentially preliminary results need to be confirmed in multicentre, randomized studies with larger sample sizes examining the use of PCT in conjunction with clinical data. Interestingly, one study has suggested that PCT has an additive prognostic value over that of the simplified acute physiology score (SAPS) II alone [58]. Additionally, more formal comparisons should be made with other blood biomarkers. Further, future studies should also attempt to determine optimal PCT measurement times and cut-offs, since these have not yet been systematically evaluated.

Ultimately, the benefits of PCT use in the management of these patients need to be established via interventional trials. Interventional investigations may do well to focus on PCT use to guide the duration of therapeutic hypothermia [59] or the aggressiveness of vasoactive therapy or artificial organ support [56].

Section snippets

Conclusions and future directions

Procalcitonin is a biochemical marker that holds great promise for the management of infectious diseases, particularly infections of the respiratory tract and sepsis. Unlike other biomarkers, interventional research has found PCT to be associated with a marked reduction in antibiotic exposure, while not increasing the risk for adverse clinical outcomes. Because patients with acute cardiovascular disease, particularly acute heart failure, may present with a similar clinical picture, PCT is also

Abbreviations

    CAP

    community-acquired pneumonia

    CHF

    congestive heart failure

    CRP

    C-reactive protein

    LRTI

    lower respiratory infection

    PCT

    procalcitonin

    WBC

    White blood cell count

Conflict of interest

PS and BM have received funding from Biomarker companies including BRAHMS/Thermofisher, BioMérieux and Roche Diagnostics. All other authors report no conflict of interest with this manuscript.

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