Iron deficiency and the effectiveness of the BNT162b2 vaccine for SARS-CoV-2 infection: A retrospective, longitudinal analysis of real-world data.

BACKGROUND: Iron plays a key role in human immune responses; however, the influence of iron deficiency on the coronavirus disease 2019 (COVID-19) vaccine effectiveness is unclear. AIM: To assess the effectiveness of the BNT162b2 messenger RNA COVID-19 vaccine in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19-related hospitalization and death in individuals with or without iron deficiency. METHODS: This large retrospective, longitudinal cohort study analyzed real-world data from the Maccabi Healthcare Services database (covering 25% of Israeli residents). Eligible adults (aged ≥16 years) received a first BNT162b2 vaccine dose between December 19, 2020, and February 28, 2021, followed by a second dose as per approved vaccine label. Individuals were excluded if they had SARS-CoV-2 infection before vaccination, had hemoglobinopathy, received a cancer diagnosis since January 2020, had been treated with immunosuppressants, or were pregnant at the time of vaccination. Vaccine effectiveness was assessed in terms of incidence rates of SARS-CoV-2 infection confirmed by real-time polymerase chain reaction assay, relative risks of COVID-19-related hospitalization, and mortality in individuals with iron deficiency (ferritin <30 ng/mL or transferrin saturation <20%). The two-dose protection period was Days 7 to 28 after the second vaccination. RESULTS: Data from 184,171 individuals with (mean [standard deviation; SD] age 46.2 [19.6] years; 81.2% female) versus 1,072,019 without (mean [SD] age 46.9 [18.0] years; 46.2% female) known iron deficiency were analyzed. Vaccine effectiveness in the two-dose protection period was 91.9% (95% confidence interval [CI] 83.7-96.0%) and 92.1% (95% CI 84.2-96.1%) for those with versus without iron deficiency (P = 0.96). Of patients with versus without iron deficiency, hospitalizations occurred in 28 and 19 per 100,000 during the reference period (Days 1-7 after the first dose), and in 19 and 7 per 100,000 during the two-dose protection period, respectively. Mortality rates were comparable between study groups: 2.2 per 100,000 (4/181,012) in the population with iron deficiency and 1.8 per 100,000 (19/1,055,298) in those without known iron deficiency. CONCLUSIONS: Results suggest that the BNT162b2 COVID-19 vaccine is >90% effective in preventing SARS-CoV-2 infection in the 3 weeks after the second vaccination, irrespective of iron-deficiency status. These findings support the use of the vaccine in populations with iron deficiency.

Intravenous iron in patients with heart failure and iron deficiency: an updated meta-analysis.

AIMS: For patients with heart failure (HF) and iron deficiency (ID), randomized trials suggest that intravenous (IV) iron reduces hospitalizations for heart failure (HHF), but uncertainty exists about the effects in subgroups and the impact on mortality. We conducted a meta-analysis of randomized trials investigating the effect of IV iron on clinical outcomes in patients with HF. METHODS AND RESULTS: We identified randomized trials published between 1 January 2000 and 5 November 2022 investigating the effect of IV iron versus standard care/placebo in patients with HF and ID in any clinical setting, regardless of HF phenotype. Trials of oral iron or not in English were not included. The main outcomes of interest were a composite of HHF and cardiovascular death (CVD), on HHF alone and on cardiovascular and all-cause mortality. Ten trials were identified with 3373 participants, of whom 1759 were assigned to IV iron. IV iron reduced the composite of recurrent HHF and CVD (rate ratio 0.75, 95% confidence interval [CI] 0.61-0.93; p < 0.01) and first HHF or CVD (odds ratio [OR] 0.72, 95% CI 0.53-0.99; p = 0.04). Effects on cardiovascular (OR 0.86, 95% CI 0.70-1.05; p = 0.14) and all-cause mortality (OR 0.93, 95% CI 0.78-1.12; p = 0.47) were inconclusive. Results were similar in analyses confined to the first year of follow-up, which was less disrupted by the COVID-19 pandemic. Subgroup analyses found little evidence of heterogeneity for the effect on the primary endpoint, although patients with transferrin saturation <20% (OR 0.67, 95% CI 0.49-0.92) may have benefited more than those with values ≥20% (OR 0.99, 95% CI 0.74-1.30) (heterogeneity p = 0.07). CONCLUSION: In patients with HF and ID, this meta-analysis suggests that IV iron reduces the risk of HHF but whether this is associated with a reduction in cardiovascular or all-cause mortality remains inconclusive.

Ferric carboxymaltose and SARS-CoV-2 vaccination-induced immunogenicity in kidney transplant recipients with iron deficiency: The COVAC-EFFECT randomized controlled trial.

Background: Kidney transplant recipients (KTRs) have an impaired immune response after vaccination against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Iron deficiency (ID) may adversely affect immunity and vaccine efficacy. We aimed to investigate whether ferric carboxymaltose (FCM) treatment improves humoral and cellular responses after SARS-CoV-2 vaccination in iron-deficient KTRs. Methods: We randomly assigned 48 iron-deficient KTRs to intravenous FCM (1-4 doses of 500mg with six-week intervals) or placebo. Co-primary endpoints were SARS-CoV-2-specific anti-Receptor Binding Domain (RBD) Immunoglobulin G (IgG) titers and T-lymphocyte reactivity against SARS-CoV-2 at four weeks after the second vaccination with mRNA-1273 or mRNA-BNT162b2. Results: At four weeks after the second vaccination, patients receiving FCM had higher plasma ferritin and transferrin saturation (P<0.001 vs. placebo) and iron (P=0.02). However, SARS-CoV-2-specific anti-RBD IgG titers (FCM: 66.51 [12.02-517.59] BAU/mL; placebo: 115.97 [68.86-974.67] BAU/mL, P=0.07) and SARS-CoV-2-specific T-lymphocyte activation (FCM: 93.3 [0.85-342.5] IFN-É£ spots per 106 peripheral blood mononuclear cells (PBMCs), placebo: 138.3 [0.0-391.7] IFN-É£ spots per 106 PBMCs, P=0.83) were not significantly different among both arms. After the third vaccination, SARS-CoV-2-specific anti-RBD IgG titers remained similar between treatment groups (P=0.99). Conclusions: Intravenous iron supplementation efficiently restored iron status but did not improve the humoral or cellular immune response against SARS-CoV-2 after three vaccinations.

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.

Fortification of salt with iron and iodine versus fortification of salt with iodine alone for improving iron and iodine status.

BACKGROUND: Iron deficiency is an important micronutrient deficiency contributing to the global burden of disease, and particularly affects children, premenopausal women, and people in low-resource settings. Anaemia is a possible consequence of iron deficiency, although clinical and functional manifestations of anemia can occur without iron deficiency (e.g. from other nutritional deficiencies, inflammation, and parasitic infections). Direct nutritional interventions, such as large-scale food fortification, can improve micronutrient status, especially in vulnerable populations. Given the highly successful delivery of iodine through salt iodisation, fortifying salt with iodine and iron has been proposed as a method for preventing iron deficiency anaemia. Further investigation of the effect of double-fortified salt (i.e. with iron and iodine) on iron deficiency and related outcomes is warranted.  OBJECTIVES: To assess the effect of double-fortified salt (DFS) compared to iodised salt (IS) on measures of iron and iodine status in all age groups. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, five other databases, and two trial registries up to April 2021. We also searched relevant websites, reference lists, and contacted the authors of included studies. SELECTION CRITERIA: All prospective randomised controlled trials (RCTs), including cluster-randomised controlled trials (cRCTs), and controlled before-after (CBA) studies, comparing DFS with IS on measures of iron and iodine status were eligible, irrespective of language or publication status. Study reports published as abstracts were also eligible. DATA COLLECTION AND ANALYSIS: Three review authors applied the study selection criteria, extracted data, and assessed risk of bias. Two review authors rated the certainty of the evidence using GRADE. When necessary, we contacted study authors for additional information. We assessed RCTs, cRCTs and CBA studies using the Cochrane RoB 1 tool and Cochrane Effective Practice and Organisation of Care (EPOC) tool across the following domains: random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; selective reporting; and other potential sources of bias due to similar baseline characteristics, similar baseline outcome assessments, and declarations of conflicts of interest and funding sources. We also assessed cRCTs for recruitment bias, baseline imbalance, loss of clusters, incorrect analysis, and comparability with individually randomised studies. We assigned studies an overall risk of bias judgement (low risk, high risk, or unclear).  MAIN RESULTS: We included 18 studies (7 RCTs, 7 cRCTs, 4 CBA studies), involving over 8800 individuals from five countries. One study did not contribute to analyses. All studies used IS as the comparator and measured and reported outcomes at study endpoint.  With regards to risk of bias, five RCTs had unclear risk of bias, with some concerns in random sequence generation and allocation concealment, while we assessed two RCTs to have a high risk of bias overall, whereby high risk was noted in at least one or more domain(s). Of the seven cRCTs, we assessed six at high risk of bias overall, with one or more domain(s) judged as high risk and one cRCT had an unclear risk of bias with concerns around allocation and blinding. The four CBA studies had high or unclear risk of bias for most domains. The RCT evidence suggested that, compared to IS, DFS may slightly improve haemoglobin concentration (mean difference (MD) 0.43 g/dL, 95% confidence interval (CI) 0.23 to 0.63; 13 studies, 4564 participants; low-certainty evidence), but DFS may reduce urinary iodine concentration compared to IS (MD -96.86 µg/L, 95% CI -164.99 to -28.73; 7 studies, 1594 participants; low-certainty evidence), although both salts increased mean urinary iodine concentration above the cut-off deficiency. For CBA studies, we found DFS made no difference in haemoglobin concentration (MD 0.26 g/dL, 95% CI -0.10 to 0.63; 4 studies, 1397 participants) or urinary iodine concentration (MD -17.27 µg/L, 95% CI -49.27 to 14.73; 3 studies, 1127 participants). No studies measured blood pressure. For secondary outcomes reported in RCTs, DFS may result in little to no difference in ferritin concentration (MD -3.94 µg/L, 95% CI -20.65 to 12.77; 5 studies, 1419 participants; low-certainty evidence) or transferrin receptor concentration (MD -4.68 mg/L, 95% CI -11.67 to 2.31; 5 studies, 1256 participants; low-certainty evidence) compared to IS. However, DFS may reduce zinc protoporphyrin concentration (MD -27.26 µmol/mol, 95% CI -47.49 to -7.03; 3 studies, 921 participants; low-certainty evidence) and result in a slight increase in body iron stores (MD 1.77 mg/kg, 95% CI 0.79 to 2.74; 4 studies, 847 participants; low-certainty evidence). In terms of prevalence of anaemia, DFS may reduce the risk of anaemia by 21% (risk ratio (RR) 0.79, 95% CI 0.66 to 0.94; P = 0.007; 8 studies, 2593 participants; moderate-certainty evidence). Likewise, DFS may reduce the risk of iron deficiency anaemia by 65% (RR 0.35, 95% CI 0.24 to 0.52; 5 studies, 1209 participants; low-certainty evidence).  Four studies measured salt intake at endline, although only one study reported this for both groups. Two studies reported prevalence of goitre, while one CBA study measured and reported serum iron concentration. One study reported adverse effects. No studies measured hepcidin concentration. AUTHORS' CONCLUSIONS: Our findings suggest DFS may have a small positive impact on haemoglobin concentration and the prevalence of anaemia compared to IS, particularly when considering efficacy studies. Future research should prioritise studies that incorporate robust study designs and outcome measures (e.g. anaemia, iron status measures) to better understand the effect of DFS provision to a free-living population (non-research population), where there could be an added cost to purchase double-fortified salt. Adequately measuring salt intake, both at baseline and endline, and adjusting for inflammation will be important to understanding the true effect on measures of iron status.

IV Sodium Ferric Gluconate Complex in Patients With Iron Deficiency Hospitalized due to Acute Heart Failure-Investigator Initiated, Randomized Controlled Trial.

ABSTRACT: Patients with heart failure (HF) with iron deficiency (ID) have worse New York Heart Association class and are at a higher risk of recurrent hospitalizations. Intravenous (IV) iron has been shown to improve exercise ability and reduce hospitalizations. IV sodium ferric gluconate complex (SFGC) has been found to be safe and affordable but has not been studied in this population in a randomized trial. This was a prospective, single-blind, investigator-initiated, randomized controlled trial. Patients admitted for acute heart failure with ID were randomly assigned 1:1 to receive IV SFGC on top of optimal medical treatment. The primary outcome was the change in the 6-minute walk test (6MWT) from baseline to 3 and 6 months. Between September 2019 and May 2021, 34 patients were randomized. 19 patients (55%) were randomized to the treatment arm receiving 125 mg of IV SFGC per day for 3-5 days. COVID-19 was a major barrier to the implementation of the study follow-up protocol, which caused the study to end early. Both groups of patients had similar clinical characteristics, comorbidities, median left ventricular ejection fraction, and rate of death and readmissions due to HF. A higher level of NT-proBNP was observed in patients treated with IV iron (7902 pg/mL vs. 3158, P = 0.04). There was no difference in 6MWT change between groups at 3 months (improvement of 21.6 vs. 24.1 meters) or 6 months (-5 meters vs. 46 meters). In conclusion, IV SFGC-treated patients had a comparable 6-minute walk at 3 and 6 months despite suffering from more severe HF with higher baseline NT-proBNP (NCT04063033).

The Influence of Nutritional Supplementation for Iron Deficiency Anemia on Pregnancies Associated with SARS-CoV-2 Infection.

Anemia is a very common occurrence during pregnancy, with important variations during each trimester. Anemia was also considered as a risk factor for severity and negative outcomes in patients with SARS-CoV-2 infection. As the COVID-19 pandemic poses a significant threat for pregnant women in terms of infection risk and access to care, we developed a study to determine the impact of nutritional supplementation for iron deficiency anemia in correlation with the status of SARS-CoV-2 infection. In a case-control design, we identified 446 pregnancies that matched our inclusion criteria from the hospital database. The cases and controls were stratified by SARS-CoV-2 infection history to observe the association between exposure and outcomes in both the mother and the newborn. A total of 95 pregnant women were diagnosed with COVID-19, having a significantly higher proportion of iron deficiency anemia. Low birth weight, prematurity, and lower APGAR scores were statistically more often occurring in the COVID-19 group. Birth weight showed a wide variation by nutritional supplementation during pregnancy. A daily combination of iron and folate was the optimal choice to normalize the weight at birth. The complete blood count and laboratory studies for iron deficiency showed significantly decreased levels in association with SARS-CoV-2 exposure. Puerperal infection, emergency c-section, and small for gestational age were strongly associated with anemia in patients with COVID-19. It is imperative to screen for iron and folate deficiency in pregnancies at risk for complications, and it is recommended to supplement the nutritional intake of these two to promote the normal development and growth of the newborn and avoid multiple complications during pregnancy in the COVID-19 pandemic setting.

Questioning Established Theories and Treatment Methods Related to Iron and Other Metal Metabolic Changes, Affecting All Major Diseases and Billions of Patients.

The medical and scientific literature is dominated by highly cited historical theories and findings [...].

A year in heart failure: an update of recent findings.

Major changes have occurred in these last years in heart failure (HF) management. Landmark trials and the 2021 European Society of Cardiology guidelines for the diagnosis and treatment of HF have established four classes of drugs for treatment of HF with reduced ejection fraction: angiotensin-converting enzyme inhibitors or an angiotensin receptor-neprilysin inhibitor, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter 2 inhibitors, namely, dapagliflozin or empagliflozin. These drugs consistently showed benefits on mortality, HF hospitalizations, and quality of life. Correction of iron deficiency is indicated to improve symptoms and reduce HF hospitalizations. AFFIRM-AHF showed 26% reduction in total HF hospitalizations with ferric carboxymaltose vs. placebo in patients hospitalized for acute HF (P = 0.013). The guanylate cyclase activator vericiguat and the myosin activator omecamtiv mecarbil improved outcomes in randomized placebo-controlled trials, and vericiguat is now approved for clinical practice. Treatment of HF with preserved ejection fraction (HFpEF) was a major unmet clinical need until this year when the results of EMPEROR-Preserved (EMPagliflozin outcomE tRial in Patients With chrOnic HFpEF) were issued. Compared with placebo, empagliflozin reduced by 21% (hazard ratio, 0.79; 95% confidence interval, 0.69 to 0.90; P < 0.001), the primary outcome of cardiovascular death or HF hospitalization. Advances in the treatment of specific phenotypes of HF, including atrial fibrillation, valvular heart disease, cardiomyopathies, cardiac amyloidosis, and cancer-related HF, also occurred. Coronavirus disease 2019 (COVID-19) pandemic still plays a major role in HF epidemiology and management. All these aspects are highlighted in this review.

COVID-19 vaccination in patients with heart failure: a position paper of the Heart Failure Association of the European Society of Cardiology.

Patients with heart failure (HF) who contract SARS-CoV-2 infection are at a higher risk of cardiovascular and non-cardiovascular morbidity and mortality. Regardless of therapeutic attempts in COVID-19, vaccination remains the most promising global approach at present for controlling this disease. There are several concerns and misconceptions regarding the clinical indications, optimal mode of delivery, safety and efficacy of COVID-19 vaccines for patients with HF. This document provides guidance to all healthcare professionals regarding the implementation of a COVID-19 vaccination scheme in patients with HF. COVID-19 vaccination is indicated in all patients with HF, including those who are immunocompromised (e.g. after heart transplantation receiving immunosuppressive therapy) and with frailty syndrome. It is preferable to vaccinate against COVID-19 patients with HF in an optimal clinical state, which would include clinical stability, adequate hydration and nutrition, optimized treatment of HF and other comorbidities (including iron deficiency), but corrective measures should not be allowed to delay vaccination. Patients with HF who have been vaccinated against COVID-19 need to continue precautionary measures, including the use of facemasks, hand hygiene and social distancing. Knowledge on strategies preventing SARS-CoV-2 infection (including the COVID-19 vaccination) should be included in the comprehensive educational programmes delivered to patients with HF.