Procalcitonin as a marker of infection in febrile neutropenia: A systematic review

Anders K. Boysen, Bettina R. Jensen, Laurids Ø. Poulsen, Paw Jensen, Søren Ladefoged

Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
Department of Hematology, Aalborg University Hospital, Aalborg, Denmark.
Department of Oncology, Aalborg University Hospital, Aalborg, Denmark.
Department of Oncology, Aarhus University Hospital, Aarhus , Denmark;.
Department of Oncology, Aarhus University Hospital, Aarhus , Denmark;Department of Oncology, Aalborg University Hospital, Aalborg, Denmark.

DOI: 10.4236/mc.2013.21002                

Abstract

Aim: Management of febrile neutropenia is challenged by lacking microbiological and clinical documentation of infection. Procalcitonin is emerging as a new promising biomarker of infection. We aimed to undertake a systematic review evaluating the diagnostic accuracy of procalcitonin as a marker of infection in febrile neutropenia. Methods: We performed a systematic re- view of the literature using the databases MEDLINE, EMBASE and Cochrane Library including a search of the grey literature (e.g. unpublished data, web sides of relevant societies). The methodological quality was assessed using predefined criteria. The relevant data were extracted and analyzed by two authors. Results: The literature search yielded a total of 193 studies of which nine were eligible for inclusion. There was a great variation in the quality of the methodological design. A notable heterogeneity exists regarding the studied populations and the definition of the reference standards. Among the nine included studies the sensitivity ranged from 42% to 72% and the specificity ranged from 64% - 89% at a cut off value ranging from 0.5 - 0.8 ng/ml. The studied endpoint was either microbiologically or clinically documented infection. Four studies found procalcitonin superior to Creactive protein in discriminating infection from the various other causes of fever. Conclusion: Procalcitonin appears to be a promising biomarker and might add new diagnostic information in the management of febrile neutropenia.

Keywords

Procalcitonin; Febrile Neutropenia

1. INTRODUCTION

Procalcitonin (PCT) is the precursor molecule of the calcium regulating hormone calcitonin, consisting of 116 amino acids and encoded by the CALC-1 gene on chromosome 11 [1]. In healthy individuals PCT is cleaved to the biologically active hormone calcitonin in the C-cells of the thyroid gland and the amount of intact PCT released to the bloodstream is usually below the detection limit. Following a stimulus of bacterial endotoxins induction extrathyroid of PCT synthesis has been reported. Multiple tissues are considered as sites of production, e.g. liver and neuroendocrine cells in the lungs [2]. PCT shows a favorable kinetic profile as a biomarker for infections with a rapid rise peaking after 6 hours, a plateau phase up to 24 hours and normalizing within 2 - 3 days, while C-reactive protein (CRP) may take up to 24 hours to peak and a plateau phase for several days followed by a slow normalizing [3,4].

Elevated levels of PCT in patients with sepsis and infection were first described in 1993 by Assicot and colleagues [5]. Within the last decades PCT has emerged as a promising marker of infection with a proposed higher sensitivity and specificity than traditional markers such as CRP [6]. The recent results have been conflicting with a meta-analysis from 2004 [7] demonstrating superior diagnostic accuracy of PCT compared to CRP in the dia- -gnosis of bacterial infections in a mixed adult and pediatric population, while a second meta-analysis from 2007 [8] examined the utility of PCT in critically ill patients and concluded that the diagnostic performance of PCT in discriminating sepsis from non-infectious causes of systemic inflammatory response syndrome (SIRS) was low.

PCT has been studied in immunocompromized patients with sepsis, first by Al-Nawas in 1996 [9] studying 55 patients with various causes of immunosuppression, e.g. hematological malignancies, chemotherapy induced neutropenia, HIV infection and following organ transplantation. They found a similar increase of PCT at the onset of sepsis compared to a group of controls with normal immune system.

Febrile neutropenia (FN) is a frequent complication following chemotherapy in hematological and oncologycal patients. FN is often defined by a temperature > 38.5˚C for 1 h and an absolute neutrophil count < 0.5 × 10⁹/L. It is a potentially life threatening condition with a mortality rate of 5% in patients with solid tumors and up to 10% in hematological malignancies [10]. Additionally, FN might have adverse affect on the overall treatment outcome due to dose reductions, treatment delays or chemotherapy discontinuation, especially in the adjuvant setting [11,12]. Management of FN is challenging due to a often lack of a clear focus of infection during physical examination [13] and a low diagnostic accuracy of the well established markers of infection (e.g. CRP) to discriminate between infection and the various other causes of fever in the adult cancer patient [14]. The most accurate way to diagnose bacterial infections is by culture [7] but the result is delayed and the incidence of bacteremia in FN is low, e.g. 10% - 20% [15,16].

PCT has been considered as a new specific marker of infection in FN. A review of the existing literature was performed in 2008 by Sakr and colleagues [17] who reviewed the literature for both adult and children includeing patients treated with high dose chemotherapy and stem cell transplantation. They concluded that PCT might be useful as a diagnostic tool in FN but due to heterogeneity no objective parameters regarding the diagnostic accuracy of PCT are available for the adult cancer patient treated with standard-dose cancer therapy. The aim of this systematic review is to identify, critically appraise and qualitative synthesize the current literature examining the diagnostic accuracy of PCT as a marker of infection in adult cancer patients presenting with FN.

2. METHODS

2.1. Literature Search

A systematic search of literature was performed in January 2012 including published papers from 1990 to 2011. The electronic databases MEDLINE, EMBASE and Cochrane library were used using the search terms: “Procalcitonin”, “Febrile neutropenia” and “immunosuppression”. Both free text and medical subject headings (MeSH) search were applied and no limitations in regard to language were used. Both observational and interventional studies were eligible for inclusion. The references of the retrieved studies were further cross-checked for potential studies missed in the electronic databases. The websites for conferences and relevant societies were examined for unpublished data and abstracts (e.g. American Society of Clinical Oncology, International Society for Infectious Disease, and American Association for Clinical Chemistry).

2.2. Study Selection and Inclusion Criteria

Two investigators (AKB and BRJ) independently performed the search and selection by initially screening the title and abstract for relevance and excluding duplicates. In the next step the relevant studies were retrieved in full text and carefully assessed in the relation to predefined inclusion and exclusion criteria before submission to data extraction. The inclusion criteria were:

1) Clinical studies evaluating the diagnostic accuracy of PCT as a marker of infection in adult patients with FN. The diagnostic accuracy must be expressed explicitly as sensitivity and specificity or presenting data making it possible for the investigators to calculate these parameters.

2) The presence of either a hematological malignancy or a solid tumor and relevant oncological treatment as the cause of neutropenia.

3) Studies examining either clinically or microbiologically documented infection as an endpoint Exclusion criteria were:

1) Studies evaluating patients treated with either autologous or allogenic stem cell transplantation 2) A pediatric study population (age < 16 y)

3) Other causes of immunosuppresion, e.g. HIV, organ transplantation in the study population Any disagreements between the authors were resolved by consensus.

2.3. Data Extraction and Quality Assessment

The following data were extracted from the included studies: Name of first author and year of publication, number of patients and FN episodes, patient population evaluated, study design, endpoint and the diagnostic accuracy of PCT as a marker of bacterial infection. A quality assessment of all included studies was performed using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) tool published in a revised version in 2011 [18]. The QUADAS-2 tool examines four domains for risk of bias: 1) patient selection, 2) index test, 3) reference test; and 4) flow and timing. The first three domains are also assessed in terms of concern of applicability. Using this tool the risk of bias is classified as either “high”, “low” or “unclear” for each domain.

To support the judgment of risk of bias, two authors (AKB and BRJ) employed specific signaling questions to each domain which could be answered “yes”, “no” or “unclear”. If all signaling questions are answered yes the risk of bias is judge as being low. If any signaling question is answered “no”, a risk of bias exists. As recommended by the QUADAS-2 guidelines [18] the applied signaling questions has been tailored to the current review and are displayed in Figure 1.

Domain 1 1) Was a consecutive or random sample of patients enrolled?

2) Was a case-control design avoided?

3) Did the study avoid inappropriate exclusions?

Domain 2 1) Did the study clearly state how PCT measurement was performed?

2) Was the threshold prespecified Domain 3 1) Was the reference standard likely to correctly classify the target condition?

2) Did the study present objective criterias for the definition of clinically documented infection?

3) Did the study define which microbiologically cultures are considered “documented infection”?

4) Was the reference standard interpreted without knowledge of the index test?   

Domain 4 1) Was there an appropriate interval between the index test and the reference standard?

2) Did all patients receive the same reference standard?

3) Were all patients included in the analysis?

Figure 1. Signaling questions for quality assessment.

Conflicts of Interest

The authors declare no conflicts of interest.

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