Procalcitonin as a Prognostic Indicator of Risk for Sepsis in the Neonate

Introduction. Procalcitonin (PCT) is a biomarker that rises at the onset of bacterial infection while remaining relatively low in other inflammatory processes. Diagnosing serious bacterial infection (SBI) in neonates presenting with fever without a source (FWS) is challenging and utilizing PCT can improve this process. This paper presents a synthesis of the evidence supporting PCT as a prognostic indicator in neonates. Methodology. A comprehensive literature review was conducted to develop practice recommendations. A guideline, the Intermountain Healthcare Care Process Model (2013), was modified to include PCT, which was then validated by a panel of clinical experts. Results. Evidence supports the use of PCT as a prognostic indicator. Clinical expert feedback supports using the modified Intermountain Healthcare Care Process Model (2013) in practice. Discussion. PCT is a valuable serum biomarker that should be examined in the workup of neonates presenting with FWS and a modified algorithm to include PCT is presented. PROCALCITONIN IN NEONATAL SEPSIS 3 Background and Significance According to the Sepsis Alliance Organization (2014), approximately 44,000 children per year develop sepsis, resulting in 4,400 deaths and sepsis is the third leading cause of death for the entire U.S. population. Sepsis is one of the most costly diseases to treat in the U.S., totaling more than $20 billion in 2011 (Agency for Healthcare Research and Quality [AHRQ], 2013). In the neonatal population, an estimated one to two incidents of sepsis occur for every 1,000 births, and for every 100 sepsis workups, about one is found to be positive (Payne, 2004). With the high cost of sepsis to patients, families, and society, early detection of SBI is essential, especially in neonates as SBI can rapidly lead to sepsis with few specific clinical signs. Sepsis in the neonate is categorized as either early onset sepsis (EOS) or late onset sepsis (LOS). EOS is sepsis occurring in the first 72 hours of life and is usually associated with the acquisition of maternal microorganisms. LOS is sepsis occurring after 72 hours of age and is usually associated with microorganisms from the environment. The early clinical signs of SBI in the neonate are nonspecific and include leukocytosis, tachycardia, and fever among others. When more specific signs are exhibited, such as hypotension, thrombocytopenia, or increased lactate levels, the patient has often already progressed to multiple organ dysfunction, and it is usually too late for life-saving measures (Wacker, Prkno, Brunkhorts, & Schlattmann, 2013). In a study of over 3,000 neonates only 58% of those with bacterial meningitis or bacteremia appeared clinically ill (Pantell et al., 2004). This lack of early specific signs of SBI may trigger providers to prescribe unnecessary antibiotics in neonates with FWS. Additionally, the concern of antibiotic overuse resulting in drug-resistant organisms may cause providers to delay treatment until a bacterial organism is more favorably suspected; if SBI is, in fact, present, such a delay can rapidly lead to shock. Further, evidence suggests antibiotic overuse has a high correlation with PROCALCITONIN IN NEONATAL SEPSIS 4 the development of lifelong irritable bowel disease (IBD) in children (Kronman, Zaoutis, Haynes, Feng, & Coffin, 2012) and is associated with newly diagnosed juvenile idiopathic arthritis (Horton et al., 2015). With the dangers inherent in delay of treatment as well as in the unnecessary use of antibiotics, prognostic indicators for the presence of SBI are essential. A neonate is usually hospitalized until cultures are negative (about 72 hours), and average daily costs associated with hospital stays per infant surpass $3,500 in the neonatal intensive care unit (Muraskas & Parsi, 2008). Certain serum biomarkers such as acute phase reactants and complete blood count (CBC) with differential are commonly used to assess for the presence of a bacterial infection. A commonly used acute phase reactant is C-reactive protein (CRP), a protein that is released by the liver during inflammatory processes such as infection and atherosclerotic disease. Erythrocyte sedimentation rate (ESR) is another acute phase reactant that is not as sensitive as CRP; CRP rises faster in an inflammatory process and falls faster during recovery (Anderson & Schmidt, 2010). Newer research indicates that another biomarker, procalcitonin, may be correlated with a bacterial infection as well. Procalcitonin (PCT) rises in the early phase of bacterial infectious processes while remaining low in viral and other inflammatory responses. PCT is mainly secreted by the liver and is a prohormone of calcitonin (England, Del Vecchio, & Aronoff, 2014). PCT was first discussed as being immunoreactive in 1983, but its exact mechanism was unclear (Hatzistilianou, 2010). There is now evidence that inflammation, specifically cytokine release during a microbial infection, may cause an upregulation of the gene expression responsible for the release of PCT from various tissues throughout the body (Hatzistilianou, 2010). Increased levels of the cytokines interleukin (IL)1β, tumor necrosis factor (TNF)-α, and IL-6 have been associated with bacterial PROCALCITONIN IN NEONATAL SEPSIS 5 infections, and are thought to induce rapid release of PCT from tissues throughout the body (Hatzistilianou, 2010; Schuetz et al., 2013; Stannard, 2014). Inversely, PCT release appears to be inhibited by interferon γ, which has been noted to elevate with viral infections (Schuetz et al., 2013; Stannard, 2014). PCT rises within 4 hours and peaks within 6 hours of bacterial infection (Mann, Wood, & Wade, 2011). CRP and white blood cell (WBC) count rise quickly but are not as specific for SBI. CRP takes 14-48 hours to change significantly after onset of infection and peaks around 18 to 72 hours of disease onset (Nasir, Mele, Babayo, & Yahaya, 2015), and though it is often higher in bacterial infections, it rises in response to most inflammatory processes such as trauma, viral, bacterial, or fungal infection, autoimmune disorders, and myocardial infarction (Pagana & Pagana, 2010). WBC levels are also nonspecific and rise in all of the aforementioned processes in addition to states such as emotional stress (Pagana & Pagana, 2010). Although CRP is more sensitive than ESR and WBC, there remains no single marker specific enough to guide clinicians on its own. With the limitations of the currently used serum biomarkers, adding the utilization of PCT levels to the workup has the potential to improve diagnostic accuracy leading to a significant improvement in patient outcomes. In healthy subjects, serum PCT levels are below 0.05 ng/mL. However, the PCT concentration with bacterial sepsis is usually much greater than 1-2 ng/mL and can increase exponentially with the degree of infection. Levels of up to 1000 ng/mL have been seen with severe bacterial sepsis. PCT levels may be elevated in viral infections, chronic inflammatory disorders, or autoimmune processes but are still generally <0.25 ng/mL (Thermo Scientific, 2013). PCT has also been found to be higher and more variable in the first three days of life (Bohnhorst et al., 2012; Shah & Padbury, 2014). With the commonly used assays, PCT results can be produced within 18 to 26 minutes (Lloyd & Kuyl, 2012; Thermo Scientific, 2013). PCT PROCALCITONIN IN NEONATAL SEPSIS 6 has been included in several European protocols for the management of febrile children, but its value is not completely defined (Gomez et al., 2012). PCT is not consistently used as a biomarker in late onset sepsis (LOS) despite its potential as a more sensitive early biomarker for SBI (Gomez et al., 2012; Stein, Schachter-Davidov, Babai, Tasher, & Somekh, 2015). According to the Health Care Blue Book (2014), the fair market price for CRP and CBC with differential are approximately $34.00 and $20.00 respectively, while the PCT test is more costly at $69.00. However, with the potential prevention of sepsis, reduction of antibiotic use, and reduced hospital stays, the higher cost of PCT is outweighed by the benefits to patients. As aforementioned, there is a high morbidity and mortality of neonatal SBI and sepsis due to their immature immune systems and immature blood brain barrier. Additionally, clinicians face great difficulty in diagnosing SBI and sepsis in the neonate due to lack of early clinical signs. Due to these difficulties, the utilization of a potentially effective biomarker such as procalcitonin should be evaluated.