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Bloodstream Infections and Iron Metabolism

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Bloodstream infections in intensive care units (ICU) are a major trigger of morbidity and mortality[1, 2]. Several risk factors for bloodstream infections in ICU have been previously established, like length of stay[3] and performance of invasive procedures, such as placement of central venous, arterial or hemodialysis catheters[4, 5], mechanical ventilation[3] and tracheostomy[6].
Additionally, it has been suggested that patients with iron deficiency could also be more susceptible to infections than those with a normal iron status[7–9]. In fact, iron is a fundamental nutrient for humans, but also a key element for bacteria growth[10–13]. Essentially, free iron in circulation promotes the release of siderophores by various bacteria, which in turn, allows the latter to compete with the host for the existing free iron. To enhance bacterial growth, the iron complexes formed are thus incorporated by receptor-mediated endocytosis[14, 15]. Moreover, evidence also suggests that a second mechanism exists for acquiring available iron in the bloodstream, through the secretion of hemolysins[16].
Iron metabolism is extensively altered by inflammation. In fact, sequestration of this element normally occurs in response to an acute inflammatory reaction, which might represent part of a defense mechanism of the human body[10]. For patients admitted to the ICU, two correlations have been established for sepsis: a direct correlation between C-reactive protein (CRP) and ferritin concentrations and an inverse correlation between CRP concentration and transferrin values in the first day of hospitalization[17]. Furthermore, Fernandez et al have demonstrated, in a small sample of ICU patients, that functional iron deficiency measured by reticulocyte hemoglobin content is associated to worst outcomes such as ICU acquired infections and higher length of stay[18, 19].
Iron is essential for normal cellular function. It is required for cell growth, proliferation, and changes in intracellular iron availability can have significant effects on cell cycle regulation, cellular metabolism, and cell division. Moreover, its balance is tightly controlled and designed to serve iron for reutilization[20]. Free iron level only partially reflects total body iron. In steady state conditions, ferritin and transferrin saturation are routinely measured to define body iron status[21]. Nevertheless, both are significantly altered during any heighten inflammatory status (acute or chronic), which frequently occurs in ICU patients. In these cases, there is usually an increase in ferritin and decrease in transferrin levels[22]. Additionally, low serum levels may lead to a state of immunodeficiency that predisposes to bloodstream infection. This relationship has been previously addressed in mice studies, although with controversial results[23].

1. Tabah A, Koulenti D, Laupland K, Misset B, Valles J, Bruzzi de Carvalho F, Paiva JA, Cakar N, Ma X, Eggimann P, Antonelli M, Bonten MJM, Csomos A, Krueger W a, Mikstacki A, Lipman J, Depuydt P, Vesin A, Garrouste-Orgeas M, Zahar J-R, Blot S, Carlet J, Brun-Buisson C, Martin C, Rello J, Dimopoulos G, Timsit J-F: Characteristics and determinants of outcome of hospital-acquired bloodstream infections in intensive care units: the EUROBACT International Cohort Study. Intensive Care Med 2012, 38:1930–45.
2. Prowle JR, Echeverri JE, Ligabo EV, Sherry N, Taori GC, Crozier TM, Hart GK, Korman TM, Mayall BC, Johnson PDR, Bellomo R: Acquired bloodstream infection in the intensive care unit: incidence and attributable mortality. Crit Care 2011, 15:R100.
3. Leon CY, Neidell M, Jia H, Sinisi M, Larson E: On the role of Length of Stay in Healthcare - Associated Bloodstream infection. Infect Control Hosp Epidemiol 2012, 33:1213–1218.
4. Safdar N, O’Horo JC, Maki DG: Arterial catheter-related bloodstream infection: incidence, pathogenesis, risk factors and prevention. J Hosp Infect 2013:1–7.
5. Brewster UC, Coca SG, Reilly RF, Perazella MA: Effect of intravenous iron on haemodialysis catheter microbial colonization and blood-borne infection. Nephrology 2005:124–128.
6. Ak O, Batirel A, Ozer S, Çolakoğlu S: Nosocomial infections and risk factors in the intensive care unit of a teaching and research hospital: a prospective cohort study. Med Sci Monit 2011, 17:PH29–34.
7. Tansarli GS, Karageorgopoulos DE, Kapaskelis A, Gkegkes I, Falagas ME: Iron deficiency and susceptibility to infections: evaluation of the clinical evidence. Eur J Clin Microbiol Infect Dis 2013: 1253–1258.
8. Hoen B: Iron and Infection: Clinical Experience. Am J Kidney Diseases 1999, 34:30–34.
9. Jurado RL: Iron, Infections, and Anemia of Inflammation. Clin Infect Dis 1997:888–895.
10. Marx JJM: Iron and infection: competition between host and microbes for a precious element. Best Practice & Research Clinical Haematology 2002, 15:411–426.
11. Bullen JJ, Rogers HJ, Spalding PB, Ward CG: Iron and infection : the heart of the matter. 2005, 43:325–330.
12. Bullen J, Griffiths E, Rogers H, Ward G: Sepsis: the critical role of iron. Microbes and infection / Institut Pasteur 2000, 2:409-415.
13. Strauss RG: Iron deficiency, infections, and immune function: a reassessment. Am J Clin Nutr 1978(April):660–666.
14. Brewster UC, Coca SG, Reilly RF, Perazella MA: Effect of intravenous iron on haemodialysis catheter microbial colonization and blood-borne infection. 2005:124–128.
15. Williams P, Griffiths E: Mini review Bacterial transferrin receptors - structure, function and contribution to virulence. Med Microbiol and Immunol 1992:301–322.
16. Mazmanian SK, Skaar EP, Gaspar AH, Humayun M, Gornicki P, Jelenska J, Joachmiak A, Missiakas DM, Schneewind O: Passage of heme-iron across the envelope of Staphylococcus aureus. Science 2003, 299:906–9.
17. Piagnerelli M, Cotton F, Herpain A, Rapotec A, Chatti R, Gulbis B, Vincent J-L: Time course of iron metabolism in critically ill patients. Acta Clin Belg, 68:22–7.
18. Fernandez R, Tubau I, Masip J, Mun L: Low Reticulocyte Hemoglobin Content is Associated with a Higher Blood Transfusion Rate in Critically Ill Patients. Anesthesiology 2010(May):1211–1215.
19. Aydogan MS, Erdogan MA, Yucel A, Toprak HI, Durmus M, Colak C: Effect of Preoperative Iron Deficiency in Liver Transplant Recipients on Length of Intensive Care Unit Stay. Transplantation proceedings 2013, 981:978–981.
20. Longo D, Fauci A, Kasper D, Hauser S, Jameson J, Loscalzo J: Harrison’s Principles of Internal Medicine. 17th edition.; 2008.
21. Punnonen K, Irjala K, Rajamäki a: Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood 1997, 89:1052–7.
22. Lapointe M: Iron supplementation in the intensive care unit : when, how much, and by what route? Crit Care 2004:37–41.
23. Zhao H, Konishi A, Fujita Y, Yagi M, Ohata K, Aoshi T, Itagaki S, Sato S, Narita H, Abdelgelil NH, Inoue M, Culleton R, Kaneko O, Nakagawa A, Horii T, Akira S, Ishii KJ, Coban C: Lipocalin 2 bolsters innate and adaptive immune responses to blood-stage malaria infection by reinforcing host iron metabolism. Cell Host Microbe 2012, 12:705–16

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