Linkage of alterations in systemic iron homeostasis to patients’ outcome in sepsis: a prospective study

Abstract

Background Sepsis, a dysregulated host response following infection, is associated with massive immune activation and high mortality rates. There is still a need to define further risk factors and laboratory parameters predicting the clinical course. Iron metabolism is regulated by both, the body’s iron status and the immune response. Iron itself is required for erythropoiesis but also for many cellular and metabolic functions. Moreover, iron availability is a critical determinant in infections because it is an essential nutrient for most microbes but also impacts on immune function and intravascular oxidative stress. Herein, we used a prospective study design to investigate the putative impact of serum iron parameters on the outcome of sepsis. Methods Serum markers of iron metabolism were measured in a prospective cohort of 61 patients (37 males, 24 females) with sepsis defined by Sepsis-3 criteria in a medical intensive care unit (ICU) and compared between survivors and non-survivors. Regulation of iron parameters in patients stratified by focus of infection and co-medication as well as association of the markers with sepsis severity scores and survival were investigated with linear and logistic regression corrected for sex and age effects. Results Positive correlations of increased serum iron and ferritin concentrations upon ICU admission with the severity of organ failure (SOFA score) and with mortality were observed. Moreover, high TF-Sat, elevated ferritin and serum iron levels and low transferrin concentrations were associated with reduced survival. A logistic regression model consisting of SOFA and transferrin saturation (SOFA–TF-Sat) had the best predictive power for survival in septic ICU patients. Of note, administration of blood transfusions prior to ICU admission resulted in increased TF-Sat and reduced survival of septic patients. Conclusions Our study could show an important impact of serum iron parameters on the outcome of sepsis. Furthermore, we identified transferrin saturation as a stand-alone predictor of sepsis survival and as a parameter of iron metabolism which may in a combined model improve the prediction power of the SOFA score. Trial registration The study was carried out in accordance with the recommendations of the Declaration of Helsinki on biomedical research. The study was approved by the institutional ethics review board of the Medical University Innsbruck (study AN2013-0006).

Analysis of Iron and Iron-Interacting Protein Dynamics During T-Cell Activation

“…Our model suggests that at such very low TSATs, T-cells are unlikely to be able to acquire sufficient iron for effective activation and differentiation. Suppression of Tf concentration from normal levels (2-3.5g/L) (22) has been observed during COVID-19 infection as well as other inflammatory states such as sepsis (48,(50)(51)(52). Suppression of Tf may be a compensatory mechanism to attempt to maintain TSAT homeostasis levels to preserve a constant rate of iron availability to the host immune system during hypoferremia.…”

Serum ferritin levels in inflammation: a retrospective comparative analysis between COVID-19 and emergency surgical non-COVID-19 patients

“…Even in most recent guidelines for COVID (COVID-19) [ 2 ] or in reports about sepsis [ 9 ], there is no mention of ferritin, transferrin, or other iron parameters. However, in a recent prospective analysis presented by Brandtner [ 10 ], iron parameters such as ferritin and transferrin saturation levels both correlate with SOFA score (Sequential Organ Failure Assessment) with a significative value: p = 0.043 and p = 0.034, respectively.…”

Pharmacological Targeting of BMP6-SMAD Mediated Hepcidin Expression Does Not Improve the Outcome of Systemic Infections With Intra-Or Extracellular Gram-Negative Bacteria in Mice

“…As these forms of anemia affect patients at increased risk of infections, the safety profile of compounds targeting Hamp transcription needs to be thoroughly assessed, as iron released from macrophages may be easily accessible to circulating microbes. The latter has been shown to be of concern in patients with impaired immune response and high iron availability, as in sepsis patients or patients after allogenic bone marrow transplantation (Petzer et al, 2019;Brandtner et al, 2020).…”

“…In 2017, an estimated 48.9 million cases of sepsis and 11 million sepsisrelated deaths were reported worldwide (Rudd et al, 2020). Bacterial infections are the most common cause of sepsis, and the severity can be partly linked to iron homeostasis as iron is an essential growth factor for many bacteria but also impacts on immune control (Ganz and Nemeth, 2015;Skaar and Raffatellu, 2015;Soares and Weiss, 2015;Brandtner et al, 2020;Valente de Souza et al, 2020). The successful withdrawal of iron by the host results in an improved infection outcome, a process called nutritional immunity (Weinberg, 1975;Skaar and Raffatellu, 2015;Gerner et al, 2020;Nairz and Weiss, 2020).…”