Iron status and the risk of sepsis and severe COVID-19: a two-sample Mendelian randomization study.

Observational studies have indicated an association between iron status and risk of sepsis and COVID-19. We estimated the effect of genetically-predicted iron biomarkers on risk of sepsis and risk of being hospitalized with COVID-19, performing a two-sample Mendelian randomization study. For risk of sepsis, one standard deviation increase in genetically-predicted serum iron was associated with odds ratio (OR) of 1.14 (95% confidence interval [CI] 1.01-1.29, P = 0.031). The findings were supported in the analyses for transferrin saturation and total iron binding capacity, while the estimate for ferritin was inconclusive. We found a tendency of higher risk of hospitalization with COVID-19 for serum iron; OR 1.29 (CI 0.97-1.72, P = 0.08), whereas sex-stratified analyses showed OR 1.63 (CI 0.94-2.86, P = 0.09) for women and OR 1.21 (CI 0.92-1.62, P = 0.17) for men. Sensitivity analyses supported the main findings and did not suggest bias due to pleiotropy. Our findings suggest a causal effect of genetically-predicted higher iron status and risk of hospitalization due to sepsis and indications of an increased risk of being hospitalized with COVID-19. These findings warrant further studies to assess iron status in relation to severe infections, including the potential of improved management.

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.

Specific changes of erythroid regulators and hepcidin in patients infected by SARS-COV-2.

Iron metabolism is tightly linked to infectious and inflammatory signals through hepcidin synthesis. To date, iron homeostasis during SARS-CoV-2 infection has not yet been described. The aim of this study is to characterize the hepcidin and erythroid regulators (growth differentiation factor 15 (GDF-15) and erythroferrone (ERFE)) by measuring concentrations in plasma in context of COVID-19 disease.We performed a single-center observational study of patients with COVID-19 to evaluate concentrations of main regulatory proteins involved in iron homeostasis, namely: hepcidin, ERFE and GDF-15. SARS-CoV-2 infection (COVID-19+) was defined by a positive RT-PCR. Sixteen patients with COVID-19+ were gender-matched and age-matched to 16 patients with a sepsis unrelated to SARS-CoV-2 (COVID-19-) and were compared with non-parametric statistic test.Clinical and hematological parameters, plasma iron, transferrin, transferrin saturation, ferritin, soluble transferrin receptor and C reactive protein were not statistically different between both groups. Median plasma hepcidin concentrations were higher in the COVID-19+ group (44.1 (IQR 16.55-70.48) vs 14.2 (IQR 5.95-18.98) nmol/L, p=0.003), while median ERFE and GDF-15 concentrations were lower in the COVID-19+ group (0.16 (IQR 0.01-0.73) vs 0.89 (IQR 0.19-3.82) ng/mL, p=0.035; 2003 (IQR 1355-2447) vs 4713 (IQR 2082-7774) pg/mL, p=0015), respectively) compared with the COVID-19- group.This is the first study reporting lower ERFE and GDF-15 median concentrations in patients with COVID-19+ compared with patients with COVID-19-, associated with an increased median concentration of hepcidin in the COVID-19+ group compared with COVID19- group.

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.

Increased serum catalytic iron may mediate tissue injury and death in patients with COVID-19.

The pathophysiology and the factors determining disease severity in COVID-19 are not yet clear, with current data indicating a possible role of altered iron metabolism. Previous studies of iron parameters in COVID-19 are cross-sectional and have not studied catalytic iron, the biologically most active form of iron. The study was done to determine the role of catalytic iron in the adverse outcomes in COVID-19. We enrolled adult patients hospitalized with a clinical diagnosis of COVID-19 and measured serum iron, transferrin saturation, ferritin, hepcidin and serum catalytic iron daily. Primary outcome was a composite of in-hospital mortality, need for mechanical ventilation, and kidney replacement therapy. Associations between longitudinal iron parameter measurements and time-to-event outcomes were examined using a joint model. We enrolled 120 patients (70 males) with median age 50 years. The primary composite outcome was observed in 25 (20.8%) patients-mechanical ventilation was needed in 21 (17.5%) patients and in-hospital mortality occurred in 21 (17.5%) patients. Baseline levels of ferritin and hepcidin were significantly associated with the primary composite outcome. The joint model analysis showed that ferritin levels were significantly associated with primary composite outcome [HR (95% CI) = 2.63 (1.62, 4.24) after adjusting for age and gender]. Both ferritin and serum catalytic iron levels were positively associated with in-hospital mortality [HR (95% CI) = 3.22 (2.05, 5.07) and 1.73 (1.21, 2.47), respectively], after adjusting for age and gender. The study shows an association of ferritin and catalytic iron with adverse outcomes in COVID-19. This suggests new pathophysiologic pathways in this disease, also raising the possibility of considering iron chelation therapy.

Association between iron status and the risk of adverse outcomes in COVID-19.

BACKGROUND & AIMS: Iron is an essential trace element to almost all organism, and the delicate balance between host defend system and viral proliferation plays an important role in infective conditions. While the association of the iron metabolism with the prognosis of COVID-19 remains poorly understood. We aimed to estimate the associations of systemic iron metabolism parameters with the severity and risks of adverse outcomes in COVID-19. METHODS: In this retrospective cohort study, we included 158 confirmed COVID-19 patients in Tongji Hospital, Wuhan, China (27 January to 5 April, 2020). Demographic data, comorbidities, laboratory examinations, treatments, and clinical outcomes were all collected. Multivariable Poisson regression was used to estimate the association of iron parameter levels with the severity and risks of adverse outcomes in COVID-19 patients. RESULTS: We identified 60 (38%) severe cases in 158 COVID-19 patients. The median age was 63 years (interquartile range [IQR]: 54-73) and the median length of hospital stay was 28 days (IQR: 17-40). After adjusting for age, sex, IL-6, and pre-existing comorbidities, all iron parameters were associated with the severity of COVID-19 with adjusted risk ratio of 0.42 [95% CI: 0.22-0.83], 4.38 [95% CI: 1.86-10.33], 0.19 [95% CI: 0.08-0.48], and 0.25 [95% CI: 0.10-0.58] for serum iron, ferritin, transferrin, and total iron-binding capacity, respectively. These iron indices were also related to the risk of ARDS, coagulopathy, acute cardiac injury, acute liver injury, and acute kidney injury in COVID-19 patients and high cytokine concentrations. CONCLUSIONS: Patients with low serum iron status likely suffered from severe condition and multiple-organ injury in COVID-19. The iron metabolism parameters might be risk factors and clinical biomarkers for COVID-19 prognosis.

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.