Serum hepcidin: indication of its role as an “acute phase” marker in febrile children

Kossiva et al. Italian Journal of Pediatrics 2013, 39:25 http://www.ijponline.net/content/39/1/25 RESEARCH ITALIAN JOURNAL OF PEDIATRICS Open Access Serum hepcidin: indication of its role as an “acute phase” marker in febrile children Lydia Kossiva1,3*, Alexandra Soldatou1, Dimitrios I Gourgiotis2, Lamprini Stamati2 and Charalampos Tsentidis1 Abstract Background: Hepcidin is classified as a type II acute phase protein; its production is a component of the innate immune response to infections. Objective: To evaluate the alterations of serum hepcidin in children during and following an acute febrile infection. Materials and methods: 22 children with fever of acute onset (< 6 hours) admitted to the 2nd Department of Pediatrics-University of Athens. Based on clinical and laboratory findings our sample formed two groups: the viral infection group (13 children) and the bacterial infection group (9 children). Hepcidin, ferritin and serum iron measurements were performed in all subjects. Results: Serum hepcidin values did not differ notably between children with viral and bacterial infection, but a significant reduction of hepcidin was noted in both groups post-infection. Conclusion: Our study provides clinical pediatric data on the role of hepcidin in the face of an acute infection. In our sample of children, hepcidin was found to rise during the acute infection and fall post-infection. Keywords: Hepcidin, Acute infection, Children, Marker Introduction Hepcidin is a cytokine-induced antimicrobial peptide produced in the liver that principally regulates the homeostasis of iron concentration. Although its production can be induced by multiple stimuli, IL-6 is considered its dominant upregulator [1]. Thus hepcidin could be classified as a type II acute phase protein. The induction of hepcidin is a component of the innate immune response to infections; it decreases extracellular iron levels reducing iron availability to invading microorganisms [2]. Most studies investigate the regulation and potential roles of hepcidin in animal models [3,4]. Although hepcidin plays a key role in the development of anaemia associated with inflammation and chronic disease, there are only a few clinical studies that examine hepcidin alterations in acute or chronic infections. However, there are not sufficient data in children to validate the use of * Correspondence: 1 Second Department of Pediatrics ‘P&A Kyriakou’ Children’s Hospital, Medical School, Athens University, Athens, Greece 3 Second Department of Pediatrics ‘P&A Kyriakou’ Children’s Hospital, Athens University, Medical School, Thivon & Levadias str, 11527 Goudi, Athens, Greece Full list of author information is available at the end of the article hepcidin levels in clinical algorithms for the diagnosis of acute infection. The evaluation and treatment of children with fever without a source is a challenging and controversial clinical problem [5]. Although most well appearing children with fever have benign viral illnesses, fever might represent the first sign of occult bacteremia and subsequent serious bacterial infection [6,7]. Discrimination based on clinical criteria has not been sufficient to determine management [8]. A number of large prospective studies have established criteria to accurately identify children warranting presumptive antibiotic therapy [9,10]. Traditional laboratory screening tests include total white blood cell count, absolute neutrophil count, band to neutrophil ratio and C-reactive protein [11-13]. The use of other acute phase reactants, such as procalcitonin and IL-6, to ameliorate the sensitivity of the screen resulted in increased use of antibiotics [14-17]. During an acute-phase reaction there are dramatic changes in iron metabolism. Previous studies have demonstrated differences in serum iron parameters in children with acute bacterial versus viral infections [18]. We hypothesized that the comparison of hepcidin levels © 2013 Kossiva et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Kossiva et al. Italian Journal of Pediatrics 2013, 39:25 http://www.ijponline.net/content/39/1/25 of children convalescing from bacterial and viral infections would not yield significant differences enhancing the role of hepcidin as an acute reactant protein. Thus the aim of the present study was to evaluate the alterations of serum hepcidin not only during the acute febrile phase but also post-infection. Materials and methods This longitudinal study was conducted during a three-year period between 2008 and 2011. Children of Greek origin and nationality participated voluntarily in the study. Informed consent from parents was obtained in advance. The Ethics Committee of our Hospital and the University of Athens Medical School approved the research protocol. Among 45 patients admitted to the 2nd Department of Pediatrics-University of Athens, 22 children were enrolled in the study. The subjects’ parents filled in a detailed questionnaire, with specific attention any history of anemia, chronic illness and folic acid or iron dietary supplementation. Children receiving antibiotic treatment or dietary iron supplementation as well as children with history of chronic disease or other co-morbidities were excluded from the study (18 patients). The remaining 5 febrile patients were also excluded since their infection could not be classified as viral or bacterial. All participating children underwent thorough physical examination. The study population consisted of 22 infants and children (13 boys, mean age 28.06 ± 37.64 months, range 1 to 144 months) presenting with fever of acute onset (< 6 hours). Full blood count with differential, routine biochemical studies, C-reactive protein, hepcidin, ferritin and serum iron measurements were performed in all subjects at the time of presentation and 4 weeks later, using standard methods by the same laboratory. The hepcidin concentration samples were stored at -80°C for 5 to 10 months before analysis. Serum hepcidin-25 isoform measurements were performed by using a specific ELISA kit (DRG INTERNATIONAL Inc. 1167 U.S Highway 22 East, Mountainside, NJ 07092 USA) according to the manufacturer’s instructions [19]. Based on clinical and laboratory findings our sample was divided into two groups: the viral infection group (13 children) and the bacterial infection group (9 children). The discrimination between bacterial and viral infection was based on the combination of positive blood or urine culture along with C-reactive protein >40 mg/dl and leukocytosis with neutrophilia (white blood cell count >15.000/mm3, neutrophils >60%). The bacterial pathogens isolated were: strep. pneumoniae, Esherichia Coli, Klebsiella pneumoniae, staph aureus. T (...truncated)