Procalcitonin as a biomarker for critically ill patients with sepsis: Effects of vitamin D supplementation

Accepted Manuscript Title: Procalcitonin as a biomarker of critically ill patients with sepsis: Effects of vitamin D supplementation Authors: Thijs Wolf, Sunil J. Wimalawansa, Mohammed S. Razzaque PII: DOI: Article Number:

S0960-0760(19)30075-5 https://doi.org/10.1016/j.jsbmb.2019.105428 105428

Reference:

SBMB 105428

To appear in:

Journal of Steroid Biochemistry & Molecular Biology

Received date: Revised date: Accepted date:

11 February 2019 22 May 2019 15 July 2019

Please cite this article as: Wolf T, Wimalawansa SJ, Razzaque MS, Procalcitonin as a biomarker of critically ill patients with sepsis: Effects of vitamin D supplementation, Journal of Steroid Biochemistry and Molecular Biology (2019), https://doi.org/10.1016/j.jsbmb.2019.105428 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Procalcitonin

as

a

biomarker

of

critically

ill

patients

with

sepsis:

Effects of vitamin D supplementation Thijs Wolf 1, Sunil J. Wimalawansa 2, Mohammed S. Razzaque 1 Department of Pathology, Lake Erie College of Osteopathic Medicine, Erie, PA, USA

2

Cardio Metabolic and Endocrine Institute, North Brunswick, NJ, USA

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1

Address of correspondence:

Mohammed S. Razzaque, Department of Pathology, Lake Erie College of Osteopathic Medicine, 1858 West Grandview Boulevard, Room: B2-306, Erie, PA 16509, USA. E-mails: [email protected], [email protected]; Tel: 1 (814) 860 5127

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Abstract

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Early diagnosis of sepsis is often difficult in clinical practice, whilst it can be vital for positive patient

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outcomes in sepsis management. Any delay in diagnosis and treatment may lead to significant organ

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failure and can be associated with elevated mortality rates. Early diagnosis and effective management of sepsis not only allows for prompt antibiotic therapy and a potential reduction in mortality, it can

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also minimize the unnecessary use of antibiotics. Furthermore, vitamin D supplementation, which is

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commonly used in the intensive care units to reduce mortality, may interfere with the ability to use procalcitonin (PCT) as a means of assessing clinical progression. Early and specific diagnosis of sepsis

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can help to reduce morbidities and mortality. This paper aims to explore the diagnostic and prognostic

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value of serum levels of PCT as an early marker of sepsis and to assess whether it can be used as a guide for using antibiotic therapy. The potential toxic effects of PCT and how it influences the

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progression of patients with sepsis will be discussed. Several serum-based biomarkers such as Creactive protein, lactate, presepsin, and cytokines, such as IL-1, and IL-6 have been evaluated as early indicators of sepsis but none have been proven sensitive and/or specific enough to make a definitive diagnosis. Finally the potential benefits and disadvantages of using serum levels of PCT to diagnose and monitor patients with sepsis and septic shock will be briefly discussed. 1|P a g e

Keywords: Procalcitonin, Sepsis, Antibiotic therapy, Vitamin D, Diagnosis, Prognosis Introduction Globally, sepsis is a major cause of morbidities. A retrospective cohort study focusing on 2,901,019

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adults admitted to study hospitals from 2009 to 2014 identified 173,690 cases of sepsis (6.0% incidence) [1]. It is also one of the leading causes of death among critically ill patient [2]. Recent advances have resulted in a reduction of in-hospital mortality of septic patients from 22.2% to 17% [3]. Nevertheless, compliance with sepsis protocols remains poor, and it continues to be a costly illness to manage. Despite many research studies investigating new therapies, no significant advances

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have been made in early-detection of sepsis. Also lacking is the development of a cost-effective, step-

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wise management protocol for patients with sepsis, that can significantly curtail mortality.

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In the 1980s following the initial discovery of pro-inflammatory cytokines, sepsis was

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described as a systemic inflammatory response to a microbial pathogen [4]. In 2016, society of critical care medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM) jointly

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proposed a new definition of sepsis as a “life-threatening organ dysfunction caused by a dysregulated

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host response to infection” [5]. This new defination has abandoned the term severe sepsis and no

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longer recognizes the use of the host inflammatory response (SIRS) as an effective means of identifying sepsis. As justification for abandoning the use of SIRS as a reliable method of identifying

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septic patients, the 2016 SCCM/ESICM task force compared the SIRS criteria versus the sequential organ failure assessment score (SOFA) for diagnosing patients with sepsis. The SOFA score focuses

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on respiratory, cardiovascular, hepatic, coagulation and neurologic components to identify septic patients with possible end-organ dysfunction [6]. The 2016 SCCM/ESICM task force further identified a simplified version of the SOFA score, the "quick SOFA” (qSOFA), with 1 point assigned to three separate criteria (Table 1) [7,8]. A score 2 indicates end-organ dysfunction [5].

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Examination of health records from the University of Pittsburgh suggested that the predictive value of using the SOFA score was superior to SIRS criteria for early diagnosis of sepsis [5]. It is important to be able to formulate and recognize the clinical presentation of sepsis, although

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consideration of serum biomarkers are also a key component of formulating a definitive diagnosis. Therefore, the purpose of this review is to discuss the clinical use of procalcitonin (PCT) as a biomarker of sepsis and to evaluate the effect of vitamin D supplementation on serum PCT levels. Despite recent advances, no biomarkers have been identified with sufficient sensitivity and specificity that allow for an accurate and clinically meaningful diagnosis of sepsis [9]. Moreover,

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critically ill patients may present with similar clinical features during a mild infection as they might

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do during episodes of severe SIRS, making it difficult to diagnose and differentiate these two disorders

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clinically. Changes in body temperature, heart rate, and respiratory rate could be minimal, and none

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of these are specific to sepsis [10]. Consequently, having a specific and sensitive biomarker would be valuable for early diagnosis and management of patients with sepsis in order to reduce mortality.

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Historically blood cultures have been the gold standard for diagnosing sepsis, however the

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lenthy time to generate results is a limitation. Additionally, many patients may have already been

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prescribed antibiotics prior to arrival to the hospital, which may mask the presentation of sepsis in the blood culture. Despite an emphasis on isolating a specific micro-organism, on average, only 34% of

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blood cultures are found to be positive in septic patients [11]. Therefore, while it can be useful, relying on the bacteriological diagnosis can be misleading or too late. This highlights the importance of having

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accurate, and early diagnostic clinical biomarkers to firmly establish the diagnosis, enabling both effective and prompt management of sepsis. The cost of sepsis management is high, particularly with the continued use of parenteral broadspectrum antibiotics and their associated adverse effects. This can place a burden on hospital and

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healthcare budgets. It is estimated that 40% of patients in European and Australasian ICUs are suspected of having sepsis [12]. Therefore, reducing the duration of antibiotic treatment, minimizing sepsis-associated complications, morbidities and deaths is important. Out of 14 clinical trials that have

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studied the utility of serum PCT levels for establishing an infectious cause of sepsis, 13 resulted in positive results, and 1 was negative [13]. The primary focus of this review is to assess the use of PCT as a biomarker for sepsis in the clinical setting.

Biochemical properties of PCT

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PCT is a 116 amino acid peptide with a molecular weight of 14.5 kDa, a member of the calcitonin

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superfamily of peptides [14]. The CALC-1 gene located on the short arm of chromosome 11 is

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responsible for cleaving the initial preprocalcitonin molecule from the primary sequence of amino

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acids [15]. Subsequent proteolytic cleavage results in a mature PCT molecule (Figure 1) [16]. It is noteworthy that serum PCT concentrations are elevated during bacterial, but not during viral infections

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[17]. In addition to thyroid C-cells, PCT is also produced in some parenchymal tissue, (such as in the

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liver, lung, kidneys, adipocytes, and muscles) in response to bacterial infections. However, cells found

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in these locations lack the ability to cleave PCT into the mature form, calcitonin molecules, leading to a blockage in the molecular pathway and an accumulation of PCT in serum. Therefore, despite a rise

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in PCT, serum calcitonin concentrations remain normal throughout the course of an infection and do not carry the same prognostic value [18]. In the absence of a bacterial infection virtually most of the

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PCT that is produced by thyroid C-cells is converted into calcitonin, explaining why baseline PCT concentrations are within normal limits. In healthy subjects, plasma PCT concentrations are less than 0.1ng/mL, but typically rises to levels >1 ng/mL during bacterial infections [19]. In order to exclude sepsis in the clinical setting, a

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cut-off concentration value of less than 0.5 ng/mL is used [20,21]. One with below this value is unlikely to have sepsis. In the absence of infection, PCT is only produced in the thyroid gland as the precursor molecule to calcitonin. The exact function of having elevated serum PCT concentrations

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during bacterial infections is still unclear [22]. Nevertheless, PCT’s half-life of 25-30 hours, coupled with its absence in healthy populations, provides it with a benefit over other biomarkers in the diagnosis of sepsis [22]. One study noted that monocytic cells produce PCT ex vivo during bacterial infection [23]. In patients with severe renal dysfunction the clearance rate of PCT may be prolonged by between one third to a half. However, this has been found to not create a clinically significant rise

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Commonly used clinical biomarkers of sepsis

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in serum levels [23].

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More researches have recently been conducted to assess relevant biomarkers of sepsis because the clinical presentation of septic patients can often be ambiguous. These serum markers provide a more

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reliable way of assessing not only the presence, but also the severity of bacterial infections. In addition

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to PCT, other biomarkers have been examined to identify sepsis, such as C-reactive protein (CRP),

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lactate, presepsin and CD14 [24,25]. The specificity of CRP as a marker for sepsis is low, and the peak serum concentrations seen during a bacterial infection do not reflect the severity of the disease.

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Furthermore, CRP levels can be elevated in several other types of infections, including systemic fungal infections and other inflammatory conditions, even when a patient is immunocompromised [26]. In

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addition to infection, there are several other conditions that may cause an elevation in CRP, such as surgery, burns, inflammatory diseases or advanced cancer [27]. As a result, CRP is not considered a useful diagnostic tool for sepsis [23,28,29]. Several studies have concluded that another biomarker, presepsin, a fragment of a cluster of differentiation marker 14 (CD14), can be used as an accurate

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biomarker for the diagnosis for sepsis [30,31]. Using 600pg/mL as a cut-off value, the specificity of presepsin for the diagnosis of sepsis was found to be 78.5% and the sensitivity was 87.8% [32]. Despite promising results in preliminary studies, there have been no multicenter studies addressing the clinical

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value of presepsin in identifying sepsis, and thus, more research is needed. Lactate is another marker that is commonly used to guide the diagnosis of sepsis and septic shock [33]. It is a biproduct of anaerobic metabolism incurred due to incomplete perfusion of vital organs, possible sequelae of sepsis. However, lactate concentrations do not clearly differentiate septic from non-septic shock [34].

TLR4, a transmembrane protein that is part of the toll-like receptor family has also been

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implicated in the pathogenesis of sepsis [35]. Signaling via TLR4 has been proposed as another

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pathway in the formation of sepsis through its generation of inflammatory mediators [36]. Despite

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this, a clinical trial of 1800 septic patients with a TLR4 antagonist (Eritoran) was abandoned because

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of lack of efficacy [36]. These data suggest that the true cause of sepsis still eludes us, and more

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research is needed to push towards more efficient methods of diagnosis and management.

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PCT as a biomarker for sepsis

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A useful biomarker for sepsis should have the following characteristics: (a) add value to the clinical evaluation, (b) shorten the time to a definitive diagnosis and (c) differentiate infectious from non-

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infectious causes [37]. For bacterial infections like endotoxins and inflammatory cytokines, current diagnostic markers, such as tumor necrosis factor alpha, IL-1, and IL-6, are typically absent within the

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first 24 hours, whereas PCT can begin to rise as early as 2 to 4 hours post-infection and peaks between 8 to 24 hours [23,38]. There are, however, several studies that have found PCT to be more effective clinical biomarker for the early detection of sepsis [39,40]. Rapid diagnosis of sepsis and bacteremia is crucial, especially in ICUs and emergency

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departments, when culture results typically take 12 to 48 hours to return [41]. The difficulty lies in the 2 to 4 hours lag time it takes for PCT to show up in a patient’s blood following the onset of sepsis. This typically, this precludes the use of PCT in the emergency department. However, upon a patient’s

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admission to the hospital with suspected sepsis, PCT could serve as an early marker to guide appropriate management. PCT has the benefit of not only indicating sepsis but may also aid in excluding sepsis. Two studies have found that the negative predictive value (NPV) of PCT is 98% and 88%, respectively [19,41] and the positive predictive value is 94% [19]. The negative predictive value of PCT was only found to be useful when serum PCP concentrations are within normal limits (<

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0.1ng/ml) [42]. Moreover, PCT was found to be particularly useful if there is a serial trend to follow.

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In septic patients with poor outcomes, PCT levels tend to increase progressively despite appropriate

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clinical management [42]. It is possible in certain situations, such as post-operatively, that serum PCT

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concentrations can remain elevated for 24 hours without an active infection being present before returning to normal. If an infection is present, PCT will continue to remain above normal limits,

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beyond 24 hours [42]. Thus, many studies recommend using a diagnostic threshold of more than 2

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ng/mL in order to reliable diagnose sepsis; values < 0.5 ng/mL rendere sepsis far less likely [20,21].

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The difficulty with any biomarker of inflammation is in the overlap of values that can be noted between patients. A closer inspection of research data reveals that although there are studies with statistically

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significant increases in serum PCT concentrations following bacterial infections, commonly there is an area of overlap with patients that did not have an infection. Thus, patients with a slight elevation

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in serum PCT concentrations may present with values that can no longer be accepted as accurate. Therefore, it is necessary for further research to define an accepted value to define the utility of PCT more precisely. Despite the promising research suggesting a role for PCT in sepsis diagnosis and management,

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its utility is only as good as the clinical accuracy of the clinician making the diagnosis. The diagnosis of sepsis is frequently uncertain, often overlapping with SIRS. Therefore, a diagnosis of sepsis requires a combination of evaluating serum-based biomarker concentrations and efficient clinical judgment to

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facilitate accurate identification of the infectious sources. There are studies that question the accuracy and utility of PCT in bacterial infections. A study conducted by Delevaux and his colleagues in 2003 divided 173 patients into documented bacterial (n=59) versus abacterial inflammation (n=113) infections in order to assess serum PCT concentrations with a cutoff value of >0.5 ng/mL. The authors concluded that only 65% of the patients with bacterial infections met their cutoff value [43]. They

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further discussed that PCT can be utilized to differentiate between bacterial infections without a

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causative organism and other strictly inflammatory processes that are also presenting with an elevation

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of classic inflammatory markers, such as CRP, IL-1 and IL-6. Alltogether, this data supports the

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utility of PCT as an effective adjunctive tool to establish an accurate diagnosis of sepsis.

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Value of PCT levels as a guide for antibiotic therapy

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The development of antibiotic-resistant organisms necessitates a need for limiting unnecessary

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antibiotic therapy in patients with bacterial infections. A recent study estimates that upwards of 30 to50% of antibiotics administered to hospitalized patients may be given unnecessarily [44]. The CDC

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study proposed that a 30% reduction in broad-spectrum antibiotic use could reduce the incidence of Clostridium Difficile infections by 26% and overall antibiotic use by 5%. Within the global healthcare

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system, there is a need to limit unnecessary antibiotic therapy. Antibiotic resistance, particularly related to the misuse of antibiotics is one of the major global health concerns. Several studies have indicated positive results in the use of PCT as a way to reduce or discontinue the use of antibiotics [45]. The PRORATA trial in 2010 was designed to come-up with an algorithm that would allow PCT-

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guided therapy to become a way of reducing antibiotic exposure in intensive care units. The study was conducted as a multicenter, prospective, parallel group, open-label trial that used a computer generated system to assign patients in a 1:1 ratio to a PCT group (n=307) versus a control group (n=314) [13].

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The trial concluded that mortality in the PCT-guided group was non-inferior to the control group at day 28 despite the PCT-guided group receiving significantly fewer days of antibiotic therapy (11.6 days, SD 8.2) versus the control group (14.3 days, SD 9.1); 95% CI 1.4 - 4.1.

Moreover, a large meta-analysis looking at 5,486 ICU adults found that using PCT-guided antibiotic therapy reported no effect on 28-day mortality, but reduced the duration of antibiotic

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therapy. The study divided participants into two groups, one that used PCT-guided therapy (n=2,748)

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and a control group (n=2,738) that used standard therapy. The meta-analysis focused on 15 studies,

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and, of the studies that assessed the duration of antibiotic treatment, an approximate 2-day reduction

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in therapy was noted (CI 2.51 to −1.15, P < 0.001) [46]. However, there had been several studies that found no benefit from PCT concentrations/assay [47–49]. In a study of lower respiratory tract bacterial

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infections, the use of PCT to guide antibiotic therapy resulted in a 39% reduction of antibiotic use

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versus standard therapy. Authors concluded that on average PCT-guided therapy resulted in a 12-hour

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decreases in the duration of treatment [50]. Nobre et al. in 2014 noted a reduction from 10 days of antibiotic therapy using a standard protocol to 6 days of antibiotic therapy in septic patients in the ICU

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who were receiving PCT-guided therapy (p=0.003). The study randomly assigned patients into an intervention group for whom antibiotic therapy ceased once PCT levels had decreased by 90% from

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their initial value. This was, however, not before day 3 (if baseline PCT is < 1 mcg/L) or day 5 (if baseline PCT ≥ 1 mcg/L). The control group, also randomly assigned, received antibiotic therapy based upon empiric guidelines [51]. Besides the reduction in antibiotic therapy, mortality and the recurrence of infection proved similar between the two groups [51]. PCT has also been studied in the neonatal

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population. Stocker et al. studied 1,700 patients with neonatal sepsis and half were treated with PCTguided antibiotic therapy and other others, with standard therapy; the authors concluded that on average PCT-guided therapy resulted in a 12-hour decreases in the duration of treatment. These

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studies support the possibility of using PCT as a way of limiting unnecessary admistration of antibiotics in patients with bacterial infections.

Prognostic value of using serum PCT concentrations

In addition to its use as a diagnostic marker of a bacterial infection, serum PCT concentrations may

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also be utilized to assess the prognosis of sepsis and persons with septic shock. Severely septic patients

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have a 30-day mortality rate of 25 to 35%, and those with septic shock, mortality is as high as 40 to

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55% [52]. A study conducted in Germany, based upon the old sepsis criteria including severe sepsis,

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found the average serum PCT concentrations to be 0.5 ± 2.9 ng/mL in sepsis patients, 6.9 ± 3.9 ng/mL for severe sepsis and 12.9 ± 4.4 ng/ml for septic shock. The authors concluded that higher serum PCT

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concentrations are indicative of a more severe infectious process [53]. Another study found that

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treatment with PCT-reactive antiserum was effective in increasing survival rates in septic animals [54].

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This study has provided hope that with more pharmaceutical research and development, targeting immunotherapy towards PCT may benefit sepsis patients.

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A retrospective chart review of male and female patients, aged between 20 to 79 years of age (n=364), containing ICD-9 or 10 codes with the diagnosis of sepsis, severe sepsis, or septic shock, was

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conducted for the period from 2014 to 2016. It displayed a positive correlation between serum PCT concentrations and SOFA scores (p =<0.001), illustrating that when the serum PCT concentrations rise, end-organ dysfunction/failure worsened [55]. The same study also found a statistically significant difference in mean serum PCT concentrations between patients with sepsis (9.6 ± 22.7) versus septic

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shock patients necessitating vasopressors to maintain their blood pressure (32.7 ± 52.2). Currently, there is inconclusive data to support the prognostic ability of PCT. As discussed above, the majority of research suggests that trending PCT appears to have a greater benefit than a

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single measurement at the time of diagnosis. A recent meta-analysis study (n=6,007) concluded that although it may not be beneficial to solely use serial PCT measurements to guide treatment, when used alongside clinical assessments of the patient they aided the prognosis [56]. Also, the effects of other drugs and nutritional supplements on the PCT level are not yet clearly defined.

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Benefit of vitamin D supplementation in bacterial infections

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The sunlight-induced vitamin D synthesis starts in the skin, and continues further to generate

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biologically active 1,25 dihydroxyvitamin D3 [1,25(OH)2D3] by two sequential hydroxylations, in

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the liver to produce 25 hydroxyvitamin D [25(OH)D] and in the kidneys to produce 1,25(OH)2D3 (Figure 2) [57–59]. Of relevance, 25(OH)D insufficiency (between 20-30 ng/mL) and the

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deficiency (less than 20 ng/mL) are believed to be highly prevalent [60]. Studies have proven that

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25(OH)D has several protective effects on the immune system, regulating hormone secretion, and

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cellular proliferation and differentiation [61]. Through limiting the release of several proinflammatory mediators, 25(OH)D can minimize the host response to bacterial infections and

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reduce the overall effect on the body. A study reported that bolus dose intramuscular 25(OH)D supplementations using 300,000 IU reduced mortality in those with bacterial infections associated

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with ventilator-associated pneumonia patients [62]. In this study, 24 patients received parenteral vitamin D and 22 patients with sepsis received a placebo. Mortality in the vitamin D-treated group was 20.8% versus 50% in the placebo-treated group. Chen et al. found that septic patients in the ICU with a vitamin D deficiency had a shorter mean survival time than patients with sufficient

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(>30 ng/mL) levels of serum 25(OH)D concentrations [61]. These results have been supported by other studies that have shown that adequate concentration of serum 25(OH)D concentrations has antimicrobial and immune-modulatory effects [61,63,64]. In addition, further research works

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suggest that vitamin D can activate cathelicidin, an anti-microbial peptide present in macrophages and in polymorphonuclear leukocytes that helps to combat both gram-negative and gram-positive infections [65].

There are, however, studies that have shown no benefit to vitamin D supplementation in reducing hospital length of stay or 6-month mortality rates [66]. Amrein et al. assessed whether

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receiving vitamin D would result in a reduced length of hospital stay for ICU patients. They were

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administered, either a bolus dose of 540,000 IU of vitamin D3 (n=249) or a placebo (n=243). Those

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who received parenteral vitamin D had an average hospital stay of, 20.1 days (IQR, 12.9-39.1) versus

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be the answer to this problem [66].

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19.0 days for the placebo (IQR, 11.6-33) [66], suggesting that supra-pharmacological doses may not

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Can vitamin D supplementation influence PCT levels?

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It is possible that following supplementation with vitamin D and normalization of serum 25(OH)D concentration, PCT may no longer be recognized as a reliable marker of sepsis for an acutely ill patient.

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Vitamin D supplementation markedly reduces the formation of pro-inflammatory cytokines by parenchymal cells during infections [67]. This can down-regulate the production of PCT by

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inflammatory cells, thus damping the production of PCT. Moreover, adequate amounts of vitamin D enhance the formation of mature T-lymphocytes (T-cells) from monocytes [68]. This in part, may be due to inhibition of IL-12 and IL-10 by 1,25(OH)2D3. This is likely to produce a tolerance-promoting regulatory T-cells that has anti-inflammatory properties [69]. Larger numbers of these T-cells, could

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directly mitigate bacteria-induced increases in serum PCT concentration [70]. By reducing serum PCT levels, vitamin D may mask the diagnostic and prognostic value of PCT in the treatment of patients with sepsis and also the management of other bacterial infections.

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As mentioned, a study by Chen et al. reported that vitamin D deficient patients (< 20 ng/mL) had an average PCT of 3.2 (0.3, 12.5) vs. 0.4 (0.3, 1.3) in serum 25(OH)D concentrations in sufficient patients (>30 ng/mL) [61]. These data demonstrated a statistically significant, linear, negative correlation between serum 25(OH)D concentrations and serum PCT. It is, therefore, possible that patients with low serum 25(OH)D concentrations at the time of admission to hospital, may present

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with laboratory findings that demonstrate a more acutely ill patient, and this could have value in the

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clinical management of septic patients. Therefore, it could be prudent to assess a patient’s vitamin D

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status before stratifying treatment protocol based upon serial serum PCT trending.

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A randomized double-blind placebo clinical trial (RCT) was conducted on patients (n=46) with ventilator-associated pneumonia (VAP) to test the effect of vitamin D supplementation on PCT and

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the SOFA score [62]. The treatment group (n=24) was given a single bolus dose of 300,000 IU

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intramuscular vitamin D and compared to a placebo group (n=22), with PCT levels and SOFA scores

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assessed at baseline and on day 7 following the intervention. The study concluded that the serum PCT concentrations were significantly reduced on day 7 (p = 0.001) in the treatment group (0.02 ± 0.59

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ng/mL) compared to the placebo group (0.68 ± 1.03 ng/mL). The study found no difference in SOFA score between treatment and placebo groups (p=0.63) [62]. Another RCT of ICU patients (n=492)

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assessed clinical improvement following a single bolus dose of 540,000 IU via a nasogastric tube [66]. This study subsequently found that the group receiving vitamin D3 supplementation (n=249) showed lower serum PCT levels at day 28 (p < 0.05) [66]. Based on current research, it is known that there is a trend between the vitamin D status of a

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patient and their respective PCT levels upon admission to ICU, with patients that are deficient more likely demonstrate higher PCT levels. It is not clear whether this is a correlation or a causation, with vitamin deficiency. It, however, needs to be mentioned that hypomagnesemia is frequently observed

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in the majority of the sepsis patients [71–73]; since magnesium is an essential cofactor for the activation of vitamin D [74,75], the effectiveness of vitamin D supplementation in sepsis patients with hypomagnesemia is not clear. As discussed, there is evidence that suggests the anti-inflammatory properties of elevated PCT concentrations, but the data remains insufficient. More research is required to establish a causative relationship and to better understand the effect that vitamin D deficiency, and

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subsequent supplementation has on PCT levels in ICU patients diagnosed with sepsis.

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Limitations in PCT measurements

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Elevated serum PCT concentrations, as seen during bacterial infections, have also been reported in several other conditions, including cardiogenic shock, renal insufficiency and autoimmune diseases A 2010 study reported elevated PCT concentrations in a patient with acute adrenal

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[76–78].

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insufficiency [79]. Additionally, serum PCT concentrations have been noted in patients that do not

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have sepsis, although concentrations are usually not very high (< 2 ng/mL). Another study listed conditions such as prolonged cardiogenic shock, heat shock, severe pancreatitis [80] and

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rhabdomyolysis to have noted increased serum PCT concentrations [81]. Despite clinically correlating with the severity of bacterial infections, one study found that APACHE II and the Multiple Organ

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Dysfunction Score were more accurate predictors of fatal outcomes in surgical intensive care unit patients [82]. Furthermore, the correlation between serum PCT levels and the severity of sepsis may be partially explained by the several toxic properties of PCT. Studies have shown that PCT increases the

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expression of surface markers on neutrophils (CD14, CD16), creating a pro-inflammatory state that can worsen in already critically ill patients [83]. To assess this, experiments have evaluated the effect of adding recombinant PCT to centrifuged whole blood. TNFα is known to be a potent induced of

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PCT levels during bacterial infections, thus this self-inducting cycle could create a perpetual proinflammatory cascade in septic patients. The results demonstrated an increase in pro-inflammatory cytokines in a dose-dependent manner, with levels of TNFα found in the largest quantities [84].

Conclusion

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The primary goal of this review was to evaluate the clinical utility of serum PCT concentrations as a

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diagnostic or prognostic tool, and use as a guide for antibiotic therapy. The secondary goal was to

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assess the effects of vitamin D supplementation on serum PCT concentrations. Serum PCT levels are

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a useful diagnostic tool available to physicians that can help as a marker of sepsis, as well as other bacterial infections. However, despite a large amount of research supporting the use of serial serum

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PCT measurements for suspected patients with sepsis, it has not been supported as a clinically useful

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diagnostic tool. Nevertheless, it appears to be the best clinical biomarker available at this time, but

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should be used as an adjunctive laboratory marker alongside a patient’s clinical presentation. Further research into establishing standardized, more sensitive and specific assays for PCT,

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and identification of universal cutoff values for better utilization of serum PCT as a diagnostic tool are recommended. In addition, vitamin D supplementation has been shown to improve overall outcome

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in ICU patients. However, current research data are inconclusive regarding the prognostic ability of PCT. More research into the associated biochemical interaction is necessary to understand the relationship between serum 25(OH)D concentrations and serum PCT concentrations.

Acknowledgments 15 | P a g e

Thanks to Rufsa H. Afroze, and Sarah Ilsenbach for carefully reading the manuscript and providing useful suggestions, and to Dr. Nuraly Akimbekov of Al-Farabi Kazakh National University, Almaty (Kazakhstan) for help in drawing the illustrations. Thijs Wolf is an Osteopathic Medical

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Student (OMS III) at the Lake Erie College of Osteopathic Medicine, Erie (USA). Dr. Razzaque is a Visiting Professor at the Harvard School of Dental Medicine, Boston (USA), and an Honorary Professor at the University of Rwanda College of Medicine & Health Sciences in Kigali (Rwanda).

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dysfunction score (MODS) in systemic inflammatory response syndrome (SIRS), Yonsei Med J. 45 (2004) 29–37. doi:10.3349/ymj.2004.45.1.29. [83] J.X. Wei, A. Verity, M. Garle, R. Mahajan, V. Wilson, Examination of the effect of procalcitonin on human leucocytes and the porcine isolated coronary artery, Br. J. Anaesth. 100 (2008) 612–621. doi:10.1093/bja/aen073. [84] A.P. Liappis, K.W. Gibbs, E.S. Nylen, B. Yoon, R.H. Snider, B. Gao, K.L. Becker, Exogenous procalcitonin evokes a pro-inflammatory cytokine response, Inflamm. Res. 60 (2011) 203–207. doi:10.1007/s00011-010-0255-8. Figure 1: Schematic representation of PCT and the calcitonin superfamily precursor molecules. CCP-I represents calcitonin carboxypeptide-I. In the thyroid gland, calcitonin pro-hormone is

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cleaved into calcitonin by peptidyl-glycine-amidating-monooxygenase (PAM) [16].

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Figure 2: Simplified diagram of the diff erent sources and stages of vitamin D synthesis; modified from earlier publications [57–59]. For simplicity, only the essential steps of vitamin synthesis are

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included. VDR: vitamin D receptor.

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Table 1: Comparison of SIRS versus qSOFA scoring [7,8] SIRS* <36 or >38 >90 <4 or >12 >20 -

qSOFA** ≥22 <100 <13

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Criteria Body temperature (C) Heart rate (beats/min) White blood cells (103/L) Respiratory Rate (breaths/min) Systolic blood pressure (mmHg) Glasgow Coma Scale

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*SIRS: Systemic Inflammatory Response Syndrome **qSOFA: Quick Sepsis-Related Organ Failure Assessment

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