COVID-19 compromises iron homeostasis: Transferrin as a target of investigation.

IMPORTANCE: Since the beginning of the COVID-19 pandemic, numerous metabolic alterations have been observed in individuals with this disease. It is known that SARS-CoV-2 can mimic the action of hepcidin, altering intracellular iron metabolism, but gaps remain in the understanding of possible outcomes in other pathways involved in the iron cycle. OBJECTIVE: To profile iron, ferritin and hepcidin levels and transferrin receptor gene expression in patients diagnosed with COVID-19 between June 2020 and September 2020. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional study that evaluated iron metabolism markers in 427 participants, 218 with COVID-19 and 209 without the disease. EXPOSURES: The primary exposure was positive diagnose to COVID-19 in general population of Santo André and São Bernardo cities. The positive and negative diagnose were determinate through RT-qPCR. MAIN OUTCOMES AND MEASURES: Devido a evidências de alterações do ciclo do ferro em pacientes diagnosticados com COVID-19 e devido a corregulação entre hepcidina e receptor de transferrina, uma análise da expressão gênica deste último, poderia trazer insights sobre o estado de ferro celular. A hipótese foi confirmada, mostrando aumento da expressão de receptor de transferrina concomitante com redução do nível de hepcidina circulante. RESULTS: Serum iron presented lower values in individuals diagnosed with COVID-19, whereas serum ferritin presented much higher values in infected patients. Elderly subjects had lower serum iron levels and higher ferritin levels, and men with COVID-19 had higher ferritin values than women. Serum hepcidin was lower in the COVID-19 patient group and transferrin receptor gene expression was higher in the infected patient group compared to controls. CONCLUSIONS AND RELEVANCE: COVID-19 causes changes in several iron cycle pathways, with iron and ferritin levels being markers that reflect the state and evolution of infection, as well as the prognosis of the disease. The increased expression of the transferrin receptor gene suggests increased iron internalization and the mimicry of hepcidin action by SARS-CoV-2, reduces iron export via ferroportin, which would explain the low circulating levels of iron by intracellular trapping.

Influence of Nutritional Parameters on the Evolution, Severity and Prognosis of Critically Ill Patients with COVID-19.

This study evaluated the clinical and nutritional status, the evolution over three days, and the relationship between nutritional, inflammatory, and clinical parameters of critically ill patients with COVID-19. A longitudinal study was conducted in the Intensive Care Unit of the Virgen de las Nieves University Hospital in Granada (Spain). The study population comprised patients with a positive polymerase chain reaction test for COVID-19 presenting critical clinical involvement. Clinical outcomes were collected, and inflammatory and nutritional parameters (albumin, prealbumin, transferrin, transferrin saturation index, cholesterol, triglycerides and Controlling Nutritional Status (CONUT) score) were determined. A total of 202 critical patients with COVID-19 were selected, presenting highly altered clinical-nutritional parameters. The evolution experienced by the patients on the third day of admission was a decrease in albumin (p < 0.001) and an increase in prealbumin (p < 0.001), transferrin (p < 0.002), transferrin saturation index (p < 0.018), and cholesterol (p < 0.001). Low levels of albumin, prealbumin (on the third day) and high CONUT score (on the third day) showed an association with higher mortality. Nutritional variables were inversely correlated with clinical and inflammatory parameters. Critically ill patients with COVID-19 have poor nutritional status related to a poor prognosis of disease severity and mortality.

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.

Low transferrin levels predict heightened inflammation in patients with COVID-19: New insights.

OBJECTIVES: Mounting evidence links hyperinflammation in gravely ill patients to low serum iron levels and hyperferritinemia. However, little attention has been paid to other iron-associated markers such as transferrin. The aim of this study was to investigate the association of different iron parameters in severe COVID-19 and their relation to disease severity. SUBJECTS AND METHODS: This study involved 73 hospitalized patients with positive test results for SARS-CoV-2. Patients were classified into two groups according to symptom severity: mild and severe. Blood levels of anti-SARS-CoV-2 antibodies, interleukin 6 (IL-6), C-reactive protein (CRP), and iron-related biomarkers were measured. RESULTS: The results revealed a significant increase in IL-6, CRP, and ferritin levels and decreased transferrin and iron levels in severe COVID-19. Transferrin negatively predicted variations in IgM and IgG levels (P < 0.001), as well as 34.4% and 36.6% increase in IL-6 and CRP levels, respectively (P < 0.005). Importantly, transferrin was the main negative predictor of ferritin levels, determining 22.7% of serum variations (P < 0.001). CONCLUSION: Reduced serum transferrin and iron levels, along with the increased CRP and high ferritin, were strongly associated with the heightened inflammatory and immune state in COVID-19. Transferrin can be used as a valuable predictor of increased severity and progression of the disease.

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.

The U-shaped association of serum iron level with disease severity in adult hospitalized patients with COVID-19.

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that leads to severe respiratory failure (RF). It is known that host exposure to viral infection triggers an iron-lowering response to mitigate pathogenic load and tissue damage. However, the association between host iron-lowering response and COVID-19 severity is not clear. This two-center observational study of 136 adult hospitalized COVID-19 patients analyzed the association between disease severity and initial serum iron, total iron-binding capacity (TIBC), and transferrin saturation (TSAT) levels. Serum iron levels were significantly lower in patients with mild RF than in the non-RF group; however, there were no significant differences in iron levels between the non-RF and severe RF groups, depicting a U-shaped association between serum iron levels and disease severity. TIBC levels decreased significantly with increasing severity; consequently, TSAT was significantly higher in patients with severe RF than in other patients. Multivariate analysis including only patients with RF adjusted for age and sex demonstrated that higher serum iron and TSAT levels were independently associated with the development of severe RF, indicating that inadequate response to lower serum iron might be an exacerbating factor for COVID-19.

The relationship between serum erythropoietin, hepcidin, and haptoglobin levels with disease severity and other biochemical values in patients with COVID-19.

INTRODUCTION: Studies have shown that iron metabolism is affected by coronavirus disease 19 (COVID-19), which has spread worldwide and has become a global health problem. Our study aimed to evaluate the relationship between COVID-19 and serum erythropoietin (EPO), hepcidin, and haptoglobin (Hpt) levels with disease severity, and other biochemical values. METHODS: Fifty nine COVID-19 patients hospitalized in the intensive care unit (ICU) and wards in our hospital between March and June 2020 and 19 healthy volunteers were included in the study. Participants were divided into mild, severe, and critical disease severity groups. Group mean values were analyzed with SPSS according to disease severity, mortality, and intubation status. RESULTS: Hemoglobin (Hb) levels were significantly lower in the critical patient group (P < .0001) and deceased group (P < .0001). The red blood cell distribution width-coefficient of variation (RDW-CV) and ferritin values were significantly higher in the intubated (P = .001, P = .005) and deceased (P = .014, P = .003) groups. Ferritin values were positively correlated with disease severity (P < .0001). Serum iron levels were lower in the patient group compared with the reference range. (P < .0001). It was found that the transferrin saturation (TfSat) was lower in the patient group compared with the control group (P < .0001). It was found that the mean EPO of the deceased was lower than the control group and the survived patient group (P = .035). Hepcidin levels were found to be significantly lower in the patient group (P < .0001). Hpt values were found to be significantly lower in the intubated group (P = .004) and the deceased group (P = .042). CONCLUSION: In our study, while serum iron and hepcidin levels decreased in patients diagnosed with COVID-19, we found that EPO and Hpt levels were significantly lower in critical and deceased patient groups. Our study is the first study examining EPO and Hpt levels in patients diagnosed with COVID-19.

Anemia and iron metabolism in COVID-19: a systematic review and meta-analysis.

Iron metabolism and anemia may play an important role in multiple organ dysfunction syndrome in Coronavirus disease 2019 (COVID-19). We conducted a systematic review and meta-analysis to evaluate biomarkers of anemia and iron metabolism (hemoglobin, ferritin, transferrin, soluble transferrin receptor, hepcidin, haptoglobin, unsaturated iron-binding capacity, erythropoietin, free erythrocyte protoporphyrine, and erythrocyte indices) in patients diagnosed with COVID-19, and explored their prognostic value. Six bibliographic databases were searched up to August 3rd 2020. We included 189 unique studies, with data from 57,563 COVID-19 patients. Pooled mean hemoglobin and ferritin levels in COVID-19 patients across all ages were 129.7 g/L (95% Confidence Interval (CI), 128.51; 130.88) and 777.33 ng/mL (95% CI, 701.33; 852.77), respectively. Hemoglobin levels were lower with older age, higher percentage of subjects with diabetes, hypertension and overall comorbidities, and admitted to intensive care. Ferritin level increased with older age, increasing proportion of hypertensive study participants, and increasing proportion of mortality. Compared to moderate cases, severe COVID-19 cases had lower hemoglobin [weighted mean difference (WMD), - 4.08 g/L (95% CI - 5.12; - 3.05)] and red blood cell count [WMD, - 0.16 × 1012 /L (95% CI - 0.31; - 0.014)], and higher ferritin [WMD, - 473.25 ng/mL (95% CI 382.52; 563.98)] and red cell distribution width [WMD, 1.82% (95% CI 0.10; 3.55)]. A significant difference in mean ferritin levels of 606.37 ng/mL (95% CI 461.86; 750.88) was found between survivors and non-survivors, but not in hemoglobin levels. Future studies should explore the impact of iron metabolism and anemia in the pathophysiology, prognosis, and treatment of COVID-19.

Iron metabolism and lymphocyte characterisation during Covid-19 infection in ICU patients: an observational cohort study.

BACKGROUND: Iron metabolism and immune response to SARS-CoV-2 have not been described yet in intensive care patients, although they are likely involved in Covid-19 pathogenesis. METHODS: We performed an observational study during the peak of pandemic in our intensive care unit, dosing D-dimer, C-reactive protein, troponin T, lactate dehydrogenase, ferritin, serum iron, transferrin, transferrin saturation, transferrin soluble receptor, lymphocyte count and NK, CD3, CD4, CD8 and B subgroups of 31 patients during the first 2 weeks of their ICU stay. Correlation with mortality and severity at the time of admission was tested with the Spearman coefficient and Mann-Whitney test. Trends over time were tested with the Kruskal-Wallis analysis. RESULTS: Lymphopenia is severe and constant, with a nadir on day 2 of ICU stay (median 0.555 109/L; interquartile range (IQR) 0.450 109/L); all lymphocytic subgroups are dramatically reduced in critically ill patients, while CD4/CD8 ratio remains normal. Neither ferritin nor lymphocyte count follows significant trends in ICU patients. Transferrin saturation is extremely reduced at ICU admission (median 9%; IQR 7%), then significantly increases at days 3 to 6 (median 33%, IQR 26.5%, p value 0.026). The same trend is observed with serum iron levels (median 25.5 µg/L, IQR 69 µg/L at admission; median 73 µg/L, IQR 56 µg/L on days 3 to 6) without reaching statistical significance. Hyperferritinemia is constant during intensive care stay: however, its dosage might be helpful in individuating patients developing haemophagocytic lymphohistiocytosis. D-dimer is elevated and progressively increases from admission (median 1319 µg/L; IQR 1285 µg/L) to days 3 to 6 (median 6820 µg/L; IQR 6619 µg/L), despite not reaching significant results. We describe trends of all the abovementioned parameters during ICU stay. CONCLUSIONS: The description of iron metabolism and lymphocyte count in Covid-19 patients admitted to the intensive care unit provided with this paper might allow a wider understanding of SARS-CoV-2 pathophysiology.