Ferritin - novel uses of a well-known marker in paediatrics

Serum ferritin is one of the most widely used laboratory tests and is associated with both iron deficiency and iron overload. Currently, more and more attention is paid to the involvement of ferritin in processes other than iron metabolism. Low serum ferritin is unanimously associated with iron deficiency, while elevated serum ferritin may be a consequence of various medical conditions such as iron overload, an inflammatory process, SARS-CoV-2, organ failure, cancer, and endocrine disorders, including metabolic syndrome. We present a review of the literature on the role of ferritin in a variety of less obvious disease states in children.Copyright © 2023 Termedia Publishing House Ltd.. All rights reserved.

Ferroptosis Is a Potential Therapeutic Target for Pulmonary Infectious Diseases

Ferroptosis is a new type of iron-dependent cell death caused by lipid peroxide (LPO) accumulation and involved in disease of pulmonary infection. The dysregulation of iron metabolism, the accumulation of LPO, and the inactivation and consumption of glutathione peroxidase 4 (GPX4) are the crucial cause of ferroptosis. Pulmonary infectious diseases caused by Pseudomonas aeruginosa (PA), Mycobacterium tuberculosis (MTB), and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are associated with ferroptosis. Ferroptosis may be a potential therapeutic target for pulmonary infectious diseases. However, the mechanisms by which these infections are involved in ferroptosis and whether pulmonary infectious diseases caused by Staphylococcus aureus, Klebsiella pneumoniae, and Leishmania spp are related to ferroptosis are unclear. Accordingly, more researches are needed.Copyright © 2023 Yurong Zhang et al.

Predictive power of the natural organometallic complex ferritin - can potentiate earlier intervention in COVID-19

Treatment of COVID-19 has been a major challenge during the current pandemic. Various parameters including clinical symptoms and laboratory markers were used for predicting severity of the disease. However, limited data has been available regarding role of inflammatory markers used for monitoring the progression of the disease. Current study aimed to investigate whether serum ferritin level can be used a marker of rapid progression of the disease and if it can predict mortality in COVID-19 cases. The present study included 40 qRT-PCR positive patients who succumbed to COVID-19 as severe group, and 40 patients who were hospitalized but recovered from the disease as the mild group. Demographic details and laboratory data of the patients were obtained and evaluated retrospectively. Spearman's rank correlation was done between serum ferritin and age in patients of differing severity of the disease. Receiver operating curve (ROC) was used for identifying best cut-off level of ferritin for classification of severity. The mean age of the non-survivor (severe/critically ill group) had a tendency to be higher than the mean age of those of the survivors (mild group). Serum ferritin was significantly higher among severe COVID-19 cases compared to mild (p<0.0001). In ROC analysis area under the curve was 0.790. Here we report for the first time, a cut off value for ferritin (277 ng/ml), which can differentiate between the various hospitalization outcomes of COVID-19 patients. There was no significant association observed in age distribution with severity of the disease. Circulating ferritin level not only reflect acute phase response but rather plays critical role in inflammation of COVID-19 disease. Ferritin a natural organometallic complex is a widely available marker, that can be used for monitoring and predicting disease progression thus it can guide clinicians for the effective management of COVID-19. © 2023 Author(s).

The Relationship Between Ferroptosis and Diseases.

Ferroptosis is an iron-dependent mode of cell death. It can occur through two major pathways, exogenous (or transporter-dependent) and endogenous (or enzyme-regulated) pathways are activated by biological or chemical inducers, and glutathione peroxidase activity is inhibited, which causes intracellular iron accumulation and lipid Peroxidation. Ferroptosis is closely related to the pathological process of many diseases. How to intervene in the occurrence and development of related diseases by regulating ferroptosis has become a hot research topic. At present, studies have shown that ferroptosis is found in common diseases such as tumors, inflammatory diseases, bacterial infections, pulmonary fibrosis, hepatitis, inflammatory bowel disease, neurodegenerative diseases, kidney injury, ischemia-reperfusion injury and skeletal muscle injury. This article reviews the characteristics and mechanism of ferroptosis, and summarizes how ferroptosis participates in the pathophysiological process in various systemic diseases of the body, which may provide new references for the treatment of clinical diseases in the future.

Human pulmonary artery endothelial cells upregulate ACE2 expression in response to iron-regulatory elements: potential implications for SARS-CoV-2 infection

Background: The current Covid-19 pandemic has resulted in significant global impacts for healthcare systems and beyond. Age and or co-morbidities which are often chronic in nature are the main risk factors for severe Covid-19 infection with strong further associations with mortality. IL-6 is reported to be greatly elevated in patients with severe Covid-19 infection. As a key positive regulator for hepcidin biosynthesis this may suggest impacts for iron metabolism in these patients;elevated serum ferritin further reinforces this notion. Aim(s): To investigate the effects of IL-6 and hepcidin on ACE2 gene expression in pulmonary artery endothelial cells (PAECs). Method(s): PAECs were treated with IL-6 (1-10 ng/mL) and hepcidin (0.1-1 mug/mL). Gene expression was identified by RT-PCR and Western Blot (WB). Result(s): When challenged with either IL-6 or hepcidin, significant upregulation of ACE2 mRNA was observed in hPAECs (n= 3;*p<0.05). Significant elevated levels of ACE2 protein expression were also observed by western blot (n= 3;*p<0.05). In addition, knock-down of the ferroportin gene (SLC40A1) in these cells resulted in significant loss of ferroportin mRNA coupled with a strong significant up-regulation of ACE2 mRNA (n= 3;*p<0.05). Conclusion(s): Whilst our results demonstrate upregulation of ACE2 gene and protein in hPAECs in response to iron regulatory elements, such as hepcidin and IL-6, further studies need to be undertaken to establish if such effects result in enhanced SARS-CoV-2 infection and whether modulation of this axis may be protective.

Iron Dyshomeostasis in COVID-19: Biomarkers Reveal a Functional Link to 5-Lipoxygenase Activation.

Coronavirus disease 2019 (COVID-19) is characterized by a broad spectrum of clinical symptoms. After acute infection, some subjects develop a post-COVID-19 syndrome known as long-COVID. This study aims to recognize the molecular and functional mechanisms that occur in COVID-19 and long-COVID patients and identify useful biomarkers for the management of patients with COVID-19 and long-COVID. Here, we profiled the response to COVID-19 by performing a proteomic analysis of lymphocytes isolated from patients. We identified significant changes in proteins involved in iron metabolism using different biochemical analyses, considering ceruloplasmin (Cp), transferrin (Tf), hemopexin (HPX), lipocalin 2 (LCN2), and superoxide dismutase 1 (SOD1). Moreover, our results show an activation of 5-lipoxygenase (5-LOX) in COVID-19 and in long-COVID possibly through an iron-dependent post-translational mechanism. Furthermore, this work defines leukotriene B4 (LTB4) and lipocalin 2 (LCN2) as possible markers of COVID-19 and long-COVID and suggests novel opportunities for prevention and treatment.

Association between iron metabolism and SARS-COV-2 infection, determined by ferritin, hephaestin and hypoxia-induced factor-1 alpha levels in COVID-19 patients.

BACKGROUND: Due to the growing evidence of the importance of iron status in immune responses, the biomarkers of iron metabolism are of interest in novel Coronavirus Disease 2019 (COVID-19). The present prospective study was carried out to compare iron status indicated by levels of ferritin with the levels of two novel biomarkers related to iron homeostasis, hephaestin and hypoxia-inducible factors-1 (HIF-1α) in the serum of patients with COVID-19 in comparison with a control group. METHODS AND RESULTS: Blood samples from 34 COVID-19 patients and from 43 healthy volunteers were collected and the levels of HEPH and HIF-1α were measured by ELISA and compared with levels of serum ferritin. COVID-19 patients had higher serum levels of ferritin than those levels in control group (P < 0.0001). Conversely levels of HIF-1α and HEPH in the COVID-19 group were significantly lower than those of control group (P < 0.0001 for both). An inverse correlation between hephaestin and ferritin as well as between HIF-1α and ferritin was found among all subjects (P < 0.0001), and among COVID-19 patients, but not to statistical significance. CONCLUSION: Levels of hephaestin and HIF-1α were found to be inversely related levels of ferritin across all participants in the study, and to our knowledge this is the first report of hephaestin and HIF-1α as potential markers of iron status. Further studies are needed to corroborate the findings, utilizing a broader range of markers to monitor inflammatory as well as iron status.

IRON METABOLISM DISORDERS AND THEIR PHARMACOLOGICAL CORRECTION

The main pathological conditions characterized by disturbances of iron metabolism have been analyzed, including anemias, hemochromatosis, inflammatory, autoimmune and neurodegenerative disorders, chronic renal insufficiency, infectious diseases (including COVID-19), etc. Strategies of their pharmacological correction and risks of common adverse effects development are considered for the potential targets of pharmacotherapy and possible groups of medications including inhibitors of prolyl-4-hydroxylase, inhibitors of bone morphogenetic proteins (BMP 6), ferroportin and hepcidin activity, inhibitors of hypoxia-inducible factor (HIF-1a) and divalent metal transporter (DMT-1). Copyright © 2022 Izdatel'stvo Meditsina. All rights reserved.

Genetic regulation of iron homeostasis in sideropenic patients with mild COVID-19 disease under a new oral iron formulation: Lessons from a different perspective.

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) needs iron to replicate itself. Coronaviruses are able to upregulate Chop/Gadd153 and Arg1 genes, consequently leading to CD8 lymphocytes decrease, degradation of asparagine and decreased nitric oxide (NO), thus impairing immune response and antithrombotic functions. Little is known about regulation of genes involved in iron metabolism in paucisymptomatic patients with COVID-19 disease or in patients with iron deficiency treated with sucrosomial iron. METHODS: Whole blood was taken from the COVID-19 patients and from patients with sideropenic anemia, treated or not (control group) with iron supplementations. Enrolled patients were: affected by COVID19 under sucrosomal iron support (group A), affected by COVID-19 not under oral iron support (group B), iron deficiency not under treatment, not affected by COVID19 (control group). After RNA extraction and complementary DNA (cDNA) synthesis of Arg1, Hepcidin and Chop/Gadd153, gene expression from the 3 groups was measured by qRT-PCR. M2 macrophages were detected by cytofluorimetry using CD163 and CD14 markers. RESULTS: Forty patients with COVID-19 (group A), 20 patients with iron deficiency treated with sucrosomial iron (group B) and 20 patients with iron deficiency not under treatment (control group) were enrolled. In all the patients supported with oral sucrosomial iron, the gene expression of Chop, Arg1 and Hepcidin genes was lower than in sideropenic patients not supported with iron, M1 macrophages polarization and functional iron deficiency was also lower in group A and B, than observed in the control group. CONCLUSIONS: New oral iron formulations, as sucrosomial iron, are able to influence the expression of genes like Chop and Arg1 and to influence M2 macrophage polarization mainly in the early phase of COVID-19 disease.

Underdiagnosis of iron deficiency anaemia in HIV-infected individuals: a pilot study using soluble transferrin receptors and intensive bone marrow iron stores to improve the diagnosis.

AIM: We compared soluble transferrin receptors (sTfR), serum ferritin, mean cell volume (MCV) of red cells and the sTfR-ferritin index with the intensive method bone marrow trephine (BMT) iron stores in the diagnosis of iron deficiency anaemia (IDA) in Human Immunodeficiency Virus (HIV)-positive hospitalised participants. METHODS: In this cross-sectional study, we recruited hospitalised HIV-positive and coronavirus of 2019 (COVID-19)-negative adults with anaemia who required a bone marrow examination as part of their diagnostic workup. We measured the full blood count, ferritin, sTfR and assessed iron using the intensive method in Haemotoxylin and Eosin (H&E)-stained BMT core biopsies of consenting participants. RESULTS: Of the 60 enrolled participants, 57 were evaluable. Thirteen (22.80%) had IDA on H&E BMT iron stores assessment, and 44 (77.19%) had anaemia of chronic diseases (ACD). The sTfR and the sTfR-ferritin index had sensitivities of 61.54% and 53.85%, respectively, for IDA diagnosis. The sensitivity and specificity of ferritin was 7.69% and 92.31%, respectively. The sTfR and sTfR-ferritin index's diagnostic specificity was relatively low at 46.15% and 38.46%, respectively. CONCLUSION: In this pilot study in HIV-positive participants, the prevalence of iron deficiency using the BMT assessment was low. Both the sTfR and the sTfR-ferritin index had a better quantitative correlation to bone marrow iron stores when compared with the MCV and ferritin and, may be more accurate surrogate markers of IDA.

Iron Homeostasis in Covid-19 Hospitalised Patients

A positive association between anemia and all-cause mortality and cardiovascular mortality independent of age, gender, and history of cardiovascular diseases has been confirmed. Disturbed iron metabolism might also play a role in the prognosis of patients with COVID-19. Moreover, alterations of iron homeostasis can persist long after COVID-19 onset and could be associated with impaired physical performance. We aimed to evaluate the levels of parameters associated with iron metabolism in patients hospitalised with COVID-19 during a 1-week period. In our study, 53 patients were included and they were further divided into two groups according to the outcome: positive (recovery and discharge from hospital) or negative (aggravation, exitus, or both). Their blood samples were collected on Days 1, 3, and 7 during hospitalization and basic laboratory analyses were performed, including measurement of iron metabolism parameters. All patients had pathologically increased plasmatic levels of ferritin and decreased levels of transferrin during the whole observation period. We have not found any correlation between levels of these markers and patients' prognosis. However, levels of ferritin significantly decreased and levels of transferrin significantly increased on the seventh day only in patients with a positive outcome. Further studies with a longer observation period are warranted to evaluate the period needed for reestablishment of iron homeostasis. [ FROM AUTHOR] Copyright of Acta Facultatis Pharmaceuticae Universitatis Comenianae is the property of Sciendo and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Heat acclimation does not attenuate hepcidin elevation after a single session of endurance exercise under hot condition.

PURPOSE: We sought to determine the effects of heat acclimation on endurance exercise-induced hepcidin elevation under hot conditions. METHODS: Fifteen healthy men were divided into two groups: endurance training under hot conditions (HOT, 35 °C, n = 8) and endurance training under cool conditions (CON, 18 °C, n = 7). All subjects completed 10 days of endurance training (8 sessions in total), consisting of 60 min of continuous exercise at 50% of maximal oxygen uptake ([Formula: see text]) under their assigned environment condition. Subjects completed a heat stress exercise test (HST, 60 min exercise at 60% [Formula: see text]) to evaluate the exercise-induced thermoregulatory and hepcidin responses under hot conditions (35 °C) before (pre-HST) and after (post-HST) the training period. RESULTS: Core temperature during exercise in the post-HST decreased significantly in the HOT group compared to pre-HST (P = 0.004), but not in the CON group. The HOT and CON groups showed augmented exercise-induced plasma interleukin-6 (IL-6) elevation in the pre-HST (P = 0.002). Both groups had significantly attenuated increases in exercise-induced IL-6 in the post-HST; however, the reduction of exercise-induced IL-6 elevation was not different significantly between both groups. Serum hepcidin concentrations increased significantly in the pre-HST and post-HST in both groups (P = 0.001), no significant difference was observed between both groups during each test or over the study period. CONCLUSION: 10 days of endurance training period under hot conditions improved thermoregulation, whereas exercise-induced hepcidin elevation under hot conditions was not attenuated following the training.

Iron oxide and iron oxyhydroxide nanoparticles impair SARS-CoV-2 infection of cultured cells.

BACKGROUND: Coronaviruses usually cause mild respiratory disease in humans but as seen recently, some human coronaviruses can cause more severe diseases, such as the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the global spread of which has resulted in the ongoing coronavirus pandemic. RESULTS: In this study we analyzed the potential of using iron oxide nanoparticles (IONPs) coated with biocompatible molecules like dimercaptosuccinic acid (DMSA), 3-aminopropyl triethoxysilane (APS) or carboxydextran (FeraSpin™ R), as well as iron oxyhydroxide nanoparticles (IOHNPs) coated with sucrose (Venofer®), or iron salts (ferric ammonium citrate -FAC), to treat and/or prevent SARS-CoV-2 infection. At non-cytotoxic doses, IONPs and IOHNPs impaired virus replication and transcription, and the production of infectious viruses in vitro, either when the cells were treated prior to or after infection, although with different efficiencies. Moreover, our data suggest that SARS-CoV-2 infection affects the expression of genes involved in cellular iron metabolism. Furthermore, the treatment of cells with IONPs and IOHNPs affects oxidative stress and iron metabolism to different extents, likely influencing virus replication and production. Interestingly, some of the nanoparticles used in this work have already been approved for their use in humans as anti-anemic treatments, such as the IOHNP Venofer®, and as contrast agents for magnetic resonance imaging in small animals like mice, such as the FeraSpin™ R IONP. CONCLUSIONS: Therefore, our results suggest that IONPs and IOHNPs may be repurposed to be used as prophylactic or therapeutic treatments in order to combat SARS-CoV-2 infection.

The Relationship Between Hepcidin-Mediated Iron Dysmetabolism and COVID-19 Severity: A Meta-Analysis.

Backgrounds: Hepcidin has been identified as a systemic iron-regulatory hormone. Recent studies have suggested that iron metabolism disorders may be involved in the pathogenesis of acute respiratory distress syndrome and multiple organ dysfunction in coronavirus disease 2019 (COVID-19). Objectives: To re-evaluate the hepcidin-related iron metabolism parameters and explore the relationship between hepcidin-mediated iron dysmetabolism and COVID-19 severity. Methods: COVID-19 is classified as mild and moderate as non-severe, severe and critical as severe. A meta-analysis was conducted. Four bibliographic databases were comprehensively searched up to December 31st 2021. Results: Six unique studies with data from 477 COVID-19 patients were included. Compared to non-severe cases, severe cases had higher hepcidin (standardized mean difference (SMD), -0.39; 95% Confidence Interval (CI) [-0.76, -0.03]; P = 0.03) and ferritin (SMD, -0.84; 95% CI [-1.30, -0.38]; P = 0.0004). In five out of six studies, a total of 427 patients were tested for serum iron, and there were significant differences in their levels between severe and non-severe cases (SMD, 0.22; 95% CI [0.02, 0.41]; P = 0.03). A total of 320 patients from four out of six studies were tested for transferrin saturation, and the statistical difference was not significant (SMD, 0.06; 95% CI [-0.17, 0.28]; P = 0.64). Conclusion: Severe COVID-19 cases had higher serum levels of hepcidin and ferritin, and lower serum iron, without significant differences in transferrin saturation. Further studies are needed to verify whether targeting the hepcidin-mediated iron metabolism axis may influence the outcome and treatment of COVID-19.

Anaemia and blood transfusion in COVID patients

Background: The Severe Acute Respiratory Coronavirus 2 (SARS-CoV- 2) infection manifests itself through a wide range of clinical pictures, from the condition of asymptomatic carrier to severe respiratory insufficiencies and/or severe organ impairments, including a massive release of cytokines, an increase in the coagulation state, haemoglobin damage, dysregulation of iron homeostasis and iron overload. It has also been appreciated a normo/macrocytic anaemia in many patients, typically associated with phlogosis. In effect, the condition of inflammation deeply affects erythropoiesis through different mechanisms, both linked to an altered iron metabolism mediated by an increased production of interleukins, and caused by proinflammatory cytokines such as the interferon-γ, IL-1, IL-33 and the Tumour necrosis factor-α (TNF-α). Inflammatory cytokines, especially IL-6 and IL-1b, increase the production of hepcidin, which, by degrading ferroportin, the cellular exporter of iron, provokes a reduction in serum iron and a sequestration of iron at the macrophage level. This process deprives potential microorganisms of iron, but it can cause a typically macrocytic anaemia, also known as 'anaemia of chronic disorders'. An altered iron metabolism would therefore be expected also in the SARS-CoV-2 infection. Nevertheless, studies on alterations of the iron metabolism in this infection are still quite limited. Aims: Our study is a retrospective analysis aimed at understanding the Covid-related pathogenesis of anaemia through the data examination of patients transfused during the SARS-COV2 infection. Methods: In our Immunohematology and Transfusion Medicine Service, we have analysed the types of anaemia occurred in patients suffering from SARS-CoV-2 who have been subjected to blood transfusion in a period comprised between November 2020 and December 2021. We have evaluated data in relation to 29 patients presenting normo-macrocytic anaemia at the onset, subjected to a transfusion of prefiltered red blood cells. The analysed sample included 15 males and 14 females with an average age of 67 years (range: 40-96). Only 4 patients out of 29 had a haemorrhage at the onset. The other 25 patients did not incur into haemorrhagic episodes. Results: Average pre-transfusion blood counts have highlighted an average haemoglobin value of 7.5 g/dl (range: 6.4-9.2) with an average globular volume of 93 fL (range: 65.3-105). Patients have been transfused on average with 4 units of prefiltered red blood cells (range: 1-24). All patients presented a severe phlogosis documented by average ferritin values of 520 ng/ml (range: 355-1200) and of CRP of 8.7 mg/dl (range: 1.79-25). Summary/Conclusions: Analysed data lead us to think that, as it has been confirmed by the scarce literature on the matter, the majority of cases of anaemia associated with a SARS-CoV-2 infection has an inflammatory pathogenesis. The high values of the serum ferritin and of the CRP strengthen this hypothesis. There is surely an additional etiopathogenetic component of bone marrow inhibition on the erythrocyte maturation associated with an alteration of iron metabolism, as it can be deduced from the increase in the average globular value.

Biomarkers for iron metabolism among patients hospitalized with community-acquired pneumonia caused by infection with SARS-CoV-2, bacteria, and influenza.

Ferritin, the central iron storage protein, has attracted attention as a biomarker of severe COVID-19. Few studies have investigated regulators of iron metabolism in the context of COVID-19. The aim was to evaluate biomarkers for iron metabolism in the acute phase response to community-acquired pneumonia (CAP) caused by SARS-CoV-2 compared with CAP caused by bacteria or influenza virus in hospitalized patients. A cross-sectional study of 164 patients from the Surviving Pneumonia Cohort recruited between January 8, 2019 and May 26, 2020. Blood samples were collected at admission and analyzed for levels of C-reactive protein (CRP), ferritin, soluble transferrin receptor, erythroferrone, and hepcidin. Median (IQR) hepcidin was higher in SARS-CoV-2 with 143.8 (100.7-180.7) ng/mL compared with bacterial and influenza infection with 78.8 (40.1-125.4) and 53.5 (25.2-125.8) ng/mL, respectively. The median ferritin level was more than 2-fold higher in patients with SARS-CoV-2 compared with the other etiologies (p < 0.001). Patients with SARS-CoV-2 had lower levels of erythroferrone and CRP compared with those infected with bacteria. Higher levels of hepcidin and lower levels of erythroferrone despite lower CRP levels among patients with SARS-CoV-2 compared with those infected with bacteria indicate alterations in iron metabolism in patients with SARS-CoV-2 infection.

The Impact of Iron Dyshomeostasis and Anaemia on Long-Term Pulmonary Recovery and Persisting Symptom Burden after COVID-19: A Prospective Observational Cohort Study.

Coronavirus disease 2019 (COVID-19) is frequently associated with iron dyshomeostasis. The latter is related to acute disease severity and COVID-19 convalescence. We herein describe iron dyshomeostasis at COVID-19 follow-up and its association with long-term pulmonary and symptomatic recovery. The prospective, multicentre, observational cohort study "Development of Interstitial Lung Disease (ILD) in Patients With Severe SARS-CoV-2 Infection (CovILD)" encompasses serial extensive clinical, laboratory, functional and imaging evaluations at 60, 100, 180 and 360 days after COVID-19 onset. We included 108 individuals with mild-to-critical acute COVID-19, whereas 75% presented with severe acute disease. At 60 days post-COVID-19 follow-up, hyperferritinaemia (35% of patients), iron deficiency (24% of the cohort) and anaemia (9% of the patients) were frequently found. Anaemia of inflammation (AI) was the predominant feature at early post-acute follow-up, whereas the anaemia phenotype shifted towards iron deficiency anaemia (IDA) and combinations of IDA and AI until the 360 days follow-up. The prevalence of anaemia significantly decreased over time, but iron dyshomeostasis remained a frequent finding throughout the study. Neither iron dyshomeostasis nor anaemia were related to persisting structural lung impairment, but both were associated with impaired stress resilience at long-term COVID-19 follow-up. To conclude, iron dyshomeostasis and anaemia are frequent findings after COVID-19 and may contribute to its long-term symptomatic outcome.

Effect of Altered Iron Metabolism on Hyperinflammation and Coagulopathy in Patients with Critical COVID-19: A Retrospective Study

A novel coronavirus disease 2019 (COVID-19) outbreak has started in Wuhan, China, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The relationship between altered iron homeostasis and hyperinflammation may be hallmarks of COVID-19 disease. We aimed to compare some iron (ferritin and iron), inflammation (C-reactive protein [CRP], hemoglobin, lactate dehydrogenase [LDH], neutrophil) and coagulation (prothrombin time [PT], activated partial thromboplastin time [APTT], D-dimer, platelet) marker results of critical COVID-19 patients with healthy controls results. In this single center retrospective study, 50 critical patients diagnosed with COVID-19 were included, demographic, clinical characteristics, severity of disease and laboratory test results were elicited from electronic medical records and compared to 50 healthy people. A statistically significant increase in CRP, LDH, neutrophil, PT, APTT, D-dimer ferritin levels was observed in critical COVID-19 patients compared with healthy people while a statistically significant decrease was observed in hemoglobin and iron levels. In addition, no statistically significant change in platelet levels was observed. Ferroptosis may be a significant cause of multiple organ failure in critical COVID-19 patients. Ferroptosis inhibitors might have potential to combat ferroptosis in COVID-19. Therefore, larger studies are needed to ferroptosis in COVID-19 in vivo and in vitro.

SARS-CoV-2 Infects Red Blood Cell Progenitors and Dysregulates Hemoglobin and Iron Metabolism.

BACKGROUND: SARS-CoV-2 infection causes acute respiratory distress, which may progress to multiorgan failure and death. Severe COVID-19 disease is accompanied by reduced erythrocyte turnover, low hemoglobin levels along with increased total bilirubin and ferritin serum concentrations. Moreover, expansion of erythroid progenitors in peripheral blood together with hypoxia, anemia, and coagulopathies highly correlates with severity and mortality. We demonstrate that SARS-CoV-2 directly infects erythroid precursor cells, impairs hemoglobin homeostasis and aggravates COVID-19 disease. METHODS: Erythroid precursor cells derived from peripheral CD34+ blood stem cells of healthy donors were infected in vitro with SARS-CoV-2 alpha variant and differentiated into red blood cells (RBCs). Hemoglobin and iron metabolism in hospitalized COVID-19 patients and controls were analyzed in plasma-depleted whole blood samples. Raman trapping spectroscopy rapidly identified diseased cells. RESULTS: RBC precursors express ACE2 receptor and CD147 at day 5 of differentiation, which makes them susceptible to SARS-CoV-2 infection. qPCR analysis of differentiated RBCs revealed increased HAMP mRNA expression levels, encoding for hepcidin, which inhibits iron uptake. COVID-19 patients showed impaired hemoglobin biosynthesis, enhanced formation of zinc-protoporphyrine IX, heme-CO2, and CO-hemoglobin as well as degradation of Fe-heme. Moreover, significant iron dysmetablolism with high serum ferritin and low serum iron and transferrin levels occurred, explaining disturbances of oxygen-binding capacity in severely ill COVID-19 patients. CONCLUSIONS: Our data identify RBC precursors as a direct target of SARS-CoV-2 and suggest that SARS-CoV-2 induced dysregulation in hemoglobin- and iron-metabolism contributes to the severe systemic course of COVID-19. This opens the door for new diagnostic and therapeutic strategies.

Optimal serum ferritin level range: iron status measure and inflammatory biomarker.

This report provides perspectives concerning dual roles of serum ferritin as a measure of both iron status and inflammation. We suggest benefits of a lower range of serum ferritin as has occurred for total serum cholesterol and fasting blood glucose levels. Observations during a prospective randomized study using phlebotomy in patients with peripheral arterial disease offered unique insights into dual roles of serum ferritin both as an iron status marker and acute phase reactant. Robust positive associations between serum ferritin, interleukin 6 [IL-6], tissue necrosis factor-alpha, and high sensitivity C-reactive protein were discovered. Elevated serum ferritin and IL-6 levels associated with increased mortality and with reduced mortality at ferritin levels <100 ng mL-1. Epidemiologic studies demonstrate similar outcomes. Extremely elevated ferritin and IL-6 levels also occur in individuals with high mortality due to SARS-CoV-2 infection. Disordered iron metabolism reflected by a high range of serum ferritin level signals disease severity and outcomes. Based upon experimental and epidemiologic data, we suggest testing the hypotheses that optimal ferritin levels for cardiovascular mortality reduction range from 20 to 100 ng mL-1 with % transferrin levels from 20 to 50%, to ensure adequate iron status and that ferritin levels above 194 ng mL-1 associate with all-cause mortality in population cohorts.