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.

The Impact of Covid19 Pandemic on Transfusion Dependent -Thalassemia Management: Experience of a Single Pediatric Treatment Center

Background: Health care systems have been facing COVID19 pandemic around the world for almost two years. Transfusion dependent (TDT) beta-thalassemia patients represent a vulnerable group,totally dependent upon hospital-based services. Aim(s): Aim of the present study was to evaluate the impact of COVID19 pandemic on management of TDT patients in a single pediatric treatment center in Northern Greece. Method(s): Patient records were reviewed in order to assess changes in management before and during the 24-month pandemic in Greece (03/01/2018-29/02/2020 and 03/01/2020 -28/02/2022, respectively) in terms of transfusion volume and transfusion frequency, mean value of pretransfusional hemoglobin, as well as laboratory parameters reflecting iron overload (ferritin levels, liver and heart MRI). Result(s): The study included 28 patients, 19 male (67.8%) and 9 female (32.2%), with an age range of 8 to 21 years. Mean number of hospital visits for transfusion was 19.97 +/- 3,52/ year prior to the pandemic and 22.38 +/- 4.35/year during the pandemic (p: 0.003). Average transfusion volume was 176.18ml +/- 38.32/kg/year kappaalphai 178.67 +/- 37.64ml/kg/year, respectively (p: 0.54). With regards to hemoglobin level, mean value was 9.56 +/- 0.42g/dl prior to the pandemic and 9.45 +/- 0.48gr/dl during the pandemic period. As to iron overload, mean ferritin level was 1362.05 +/- 517.56 ng/mL prior to the pandemic and 1021.27 +/- 508.92 ng/mL during the latter time period (p:0.016). Out of 28 enrolled patients, 26 underwent heart and liver MRI before pandemic and 23 during the pandemic period. Mean LIC values were 6.84 +/- 7.37 mg/gdw and 6.43 +/- 6.46 mg/gdw (p: 0.97) before and during the pandemic, respectively (p:0.97). Myocardial MRI values were within normal limits both before and during the pandemic. Summary-Conclusion: Covid19 pandemic did not seem to negatively affect the primary goal of transfusion therapy (pretransfusion Hb), even if an increased number of visits was required in order to transfuse the same blood volume - due to limited availability of blood units per visit. Of interest, pandemic conditions appeared to favor patient adherence to chelation therapy.

Deferoxamine has the Potential to Improve the COVID-19-Related Inflammatory Response in Diabetic Patients.

The clinical state of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been considered a pandemic disease (COVID-19) that is rapidly spreading worldwide. Despite all global efforts, the only treatment for COVID-19 is supportive care and there has been no efficient treatment to fight this plague. It is confirmed that patients with chronic diseases such as cardiovascular disorder and diabetes; are more vulnerable to COVID-19. In the severe type of COVID-19, laboratory findings showed a remarkably enhanced C-reactive protein, IL-6 serum, Iron, and ferritin, which suggest an inflammatory response. Inflammation results in iron homeostasis imbalance and causes iron overload, exacerbating the SARSCOV2 infection. More importantly, recent studies have established that SARS-CoV-2 needs iron for viral replication and also activation. As a result, managing iron overload in diabetic patients with COVID-19 could be an early therapeutic approach to limit the lethal inflammatory response of COVID-19. In this review, Deferoxamine (DFO) has been proposed as an effective iron chelator agent.

Iron as a therapeutic target in chronic liver disease.

It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.

Diverse Presentation of Mucormycosis: A Post COVID Catastrophe - A Case Series

The corona virus disease-19 (COVID-19) produced by SARS-CoV-2 has resulted in a wide spectrum of illness ranging from mild to life-threatening conditions thus enhancing the incidence of opportunistic infections among individuals harbouring comorbidities. Mucormycosis is a dreadful angio-invasive opportunistic infection produced by zygomycetes fungus in an immunocompromised host. The clinical manifestations of mucormycosis include rhino-orbital-cerebral (ROC), pulmonary, cutaneous, gastrointestinal, with ROC accounting for around 40% of cases. Diabetes, neutropenia, iron overload, cancer, and organ transplant are all major culprits. Both Aspergillus and Candida have been identified as the primary fungal pathogens causing co-infection in COVID-19 preyed individuals. The most predominant variety, Rhizopus Oryzae, is responsible for roughly 60% of mucormycosis infections in humans, as well as 90% of the Rhino-orbital-cerebral (ROCM) variant. Mucormycosis is the most widespread ailment in India. Until lately, India was declared to be the world's diabetes capital, with the second-largest number of people suffering from diabetes mellitus (DM). Diabetes has been recognised as the most common predictive marker for mucormycosis which explains the dramatic rise in Mucor cases in India lately particularly during second wave of COVID-19. The inflammatory onslaught caused by COVID 19 has debilitated patients' immune systems, making individuals vulnerable to mucormycosis outbreaks. The possible explanation that Mucorales spores appear to be expediting germination in people with COVID-19 is due to the perfect scenario of oxygen deprivation (hypoxia), hyperglycemia (steroid-induced), acidic form of media (metabolic acidosis, diabetic ketoacidosis), increased iron levels (elevated ferritin), and significantly reduced phagocytic activity of white blood cells (WBC) due to immunosuppression (SARS-CoV-2 or steroid mediated or associated comorbidities). Copyright © 2022 International Medical Sciences Academy. All rights reserved.

Autoimmune Hepatitis in the Setting of Iron Overload Secondary to Heterozygous HFE Gene Mutation.

Autoimmune hepatitis (AIH) is an inflammatory condition of the liver that is characterized by high titers of certain autoantibodies in the serum. As in other chronic inflammatory conditions, the transferrin saturation in patients with AIH is typically low. However, in rare instances, AIH has been reported to be associated with elevated transferrin saturation secondary to heterozygous HFE gene (H63D) mutation. This report describes one such case in which the patient had characteristic histopathologic findings of AIH but was also found to have iron overload and heterozygous H63D mutation on genetic testing, leading to the initial dual differential diagnosis of AIH and hemochromatosis, which highlighted the further need of obtaining a liver biopsy.

Role of Biomarkers in Sepsis in ICU: An Interim Analysis of Cross-sectional Study in a Tertiary Care Hospital ABS0130)

Introduction: Sepsis is a common cause of morbidity and mortality with no gold standard diagnostic test for detecting sepsis. Blood cultures are a frequent diagnostic step but the results take at least 48 hours and timely recognition of infection and initiation of appropriate antibiotics remain crucial in the treatment of sepsis. Biomarkers thus come in handy for rapid diagnosis and risk stratification. Objectives: Primary objective: To assess the diagnostic and prognostic value of procalcitonin (PCT), interleukin-6 (IL-6), ferritin, and C-reactive protein (CRP) levels in differentiating between Gram-negative and Gram-positive sepsis patients. Secondary objective: To determine the relationship between serum PCT, IL-6, ferritin, and CRP levels and isolated sepsis pathogens. Materials and methods: We are conducting a cross-sectional study for a period of 2 years on 360 adult patients admitted in an intensive care unit (ICU) of a tertiary care hospital with sepsis or septic shock. Our exclusion criteria are patients with burns, suspected or documented non-bacterial infections, viral hepatitis, iron overload states, and active COVID-19 infection. We are using convenience sampling. Demographic details of patients are collected. Blood is drawn for estimation of the four aforementioned biomarkers as well as body fluids of the patient based on clinical suspicion are sent for microbiological evaluation on admission to ICU before administration of antibiotics. Based on the culture reports, patients are classified as culture-positive or culture-negative sepsis and the biomarkers in each group are analyzed for diagnostic and prognostic accuracy. The primary outcome of the study is the survival or death of the patient while the secondary outcome is the number of days of ICU stay. During the time of submission, only 25 patients had been recruited and an interim analysis is being conducted. Results: During the time of submission, only 25 patients had been recruited and an interim analysis is being conducted. The mean age of our patients was 57.16 years. The study population was predominantly males (20 subjects) with ten subjects of urosepsis, three with pancreatitis, two with pneumonia, and the remaining ten had a miscellaneous diagnosis. The mean values of the inflammatory markers were as follows: PCT = 16.672 (±24.3495), CRP = 85.8428 (±62.1224), IL-6 = 610.268 (±723.3846), and ferritin = 625.0832 (±628.5289). The p value of the biomarkers is <0.00001 and is significant at p < 0.05. The following combinations of biomarkers were found to be statistically significant - PCT with IL-6 (p = 0.00018), PCT with ferritin (p = 0.00012), CRP with IL-6 (p = 0.00116), and CRP with ferritin (p = 0.00079). The sensitivity of CRP and IL-6 was 100% while specificity was highest for PCT at 50%. Eight of the subjects had Gram-negative sepsis. The mean days of hospitalization were 19.92 days. Eight of the subjects died contributing to a mortality rate of 3.2 per 10 subjects. Conclusion: The combination of biomarkers reflects different aspects of sepsis pathophysiology and would be feasible to incorporate as a point of care testing. The biomarker panel that would provide diagnostic information for the investigation of a patient with suspected sepsis earlier than cultures is PCT with IL-6 and ferritin.

Hyperferritinemia, Low Circulating Iron and Elevated Hepcidin May Negatively Impact Outcome in COVID-19 Patients: A Pilot Study.

Inflammation in COVID-19 produces intracellular iron overload with low circulating iron available for metabolic processes. The accumulated intracellular iron generates reactive species of oxygen and results in ferroptosis, a non-programmed cell death. Since no organ is spared, iron dysmetabolism increases the mortality and morbidity. Hepcidin and the mediator interleukin 6 are believed to play a role in the process. Our aim is to evaluate the predictive values of serologic iron and inflammatory parameters in COVID-19 critically ill patients. Hence, 24 patients were included. Hepcidin and interleukin 6, along with routine blood parameters, were determined and outcomes, such as death, multiple organ damage (MOD), anemia, and need for transfusions, were assessed. The results of this pilot study indicate that iron metabolism parameters individually, as well as models consisting of multiple laboratory and clinical variables, may predict the outcomes. Further larger studies are needed to validate the results of this pilot stud. However, this paper identifies a new direction for research.

Transient Elastography of Liver and Serum Hyaluronic Acid Levels In Adult Transfusion Dependent Thalassemia Patients

Iron overload occurs as a result of multiple blood transfusions and increased iron absorption in thalassemia patients. Iron deposition in liver results in liver stiffness and fibrosis. Non invasive methods including imaging and serum biomarkers have been introduced for assessment of liver fibrosis. We aimed to study liver stiffness using transient elastography and serum hyaluronic acid levels and correlate them with serum ferritin levels in adult transfusion dependent beta thalassemia patients. MATERIAL: 70 transfusion dependent thalassemia patients of age ≥18 years, registered at Thalassemia Day Care Centre were subjected to investigations like CBC, Liver function tests, viral markers, serum ferritin, serum hyaluronic acid levels and transient elastography. Fibrosis indices like FIB-4, AAR and APRI were also calculated. 45 patients had T2*MRI reports with them;which were also included and analysed. Spearman coefficient r was used to test correlations between TE values and serum HA levels with other variables. OBSERVATION: 70 patients (41 male and 29 female) with mean age of 24.09±5.38 years and BMI 20.51 ±3.47 kg/m², were enrolled. Median values of hemoglobin, AST, ALT, TE, serum HA and serum ferritin were, 9.15 g/dl, 42 IU/L, 47.50 IU/L, 9.1 kPa, 284 ng/dl and 1841 ng/ml, respectively . TE values had significant positive correlation with serum ferritin (r=0.5, p < 0.001), ALT (r=0.59, p < 0.001), AST (r=0.58, p< 0.001), APRI (r=0.5, p<0.001) and FIB-4 (p=0.02), respectively and significant negative correlation with T2* MRI (ms) (r= -0.5, p<0.001). No significant correlation of HA was found with any variable. CONCLUSION: Transient elastography can be used as a non expensive, easily accessible and non invasive marker of liver iron overload. Further detailed studies are required to establish the role of serum Hyaluronic acid in thalassemia patients. © Journal of the Association of Physicians of India 2011.

Mucormycosis and COVID-19-Associated Mucormycosis: Insights of a Deadly but Neglected Mycosis.

The ongoing COVID-19 pandemic has quickly become a health threat worldwide, with high mortality and morbidity among patients with comorbidities. This viral infection promotes the perfect setting in patients for the development of opportunistic infections, such as those caused by fungi. Mucormycosis, a rare but deadly fungal infection, has recently increased its incidence, especially in endemic areas, since the onset of the pandemic. COVID-19-associated mucormycosis is an important complication of the pandemic because it is a mycosis hard to diagnose and treat, causing concern among COVID-19-infected patients and even in the already recovered population. The risk factors for the development of mucormycosis in these patients are related to the damage caused by the SARS-CoV-2 itself, the patient's overstimulated immune response, and the therapy used to treat COVID-19, causing alterations such as hyperglycemia, acidosis, endothelial and lung damage, and immunosuppression. In this review, the molecular aspects of mucormycosis and the main risk factors for the development of COVID-19-associated mucormycosis are explained to understand this virus-fungi-host interaction and highlight the importance of this neglected mycosis.

Good Clinical Practice of the Italian Society of Thalassemia and Haemoglobinopathies (SITE) for the Management of Endocrine Complications in Patients with Haemoglobinopathies.

BACKGROUND: The treatment of endocrinopathies in haemoglobinopathies is a continually expanding research area; therefore, recommendations supporting the appropriateness of treatments are a pressing need for the medical community. METHODS: The Management Committee of SITE selected and gathered a multidisciplinary and multi-professional team, including experts in haemoglobinopathies and experts in endocrinopathies, who have been flanked by experts with methodological and organizational expertise, in order to formulate recommendations based on the available scientific evidence integrated by personal clinical experience. The project followed the systematic approach for the production of clinical practice guidelines according to the methodology suggested by the National Center for Clinical Excellence, Quality and Safety of Care (CNEC). RESULTS: Out of 14 topics, 100 clinical questions were addressed, and 206 recommendations were elaborated on. The strength of recommendations, panel agreement, a short general description of the topic, and the interpretation of evidence were reported. CONCLUSIONS: Good Practice Recommendations are the final outcome of translational research and allow one to transfer to the daily clinical practice of endocrine complications in haemoglobinopathies.

Disseminated Cunninghamella spp. Endocarditis in a Beta-Thalassemia Patient after Asymptomatic COVID-19 Infection.

Cunninghamella spp. is a group of fungi belonging to the Mucorales order. Cases of fungal endocarditis are sporadic, but more frequent in immunocompromised patients. COVID-19 (SARS-CoV-2 Infection Disease 2019) infections, prematurity, deferoxamine treatment, iron overload, neutropenia, diabetes, and malignant hemopathies proved to be risk factors for mucormycosis. We present the case of a 7-year-old boy who was treated every three weeks with blood transfusion for major beta-thalassemia, receiving deferoxamine for secondary hemochromatosis. After two weeks with nonspecific respiratory and digestive symptoms, he was admitted for fever, followed by lower limb ischemia and neurological signs. Echocardiography revealed massive endocarditis affecting the mitral and tricuspid valves with embolization phenomena in the brain, lungs, kidney, spleen, and lower limbs. As a particular finding, IgG antibodies for COVID-19 were positive. Emergency cardiac surgery was performed. The mitral valve necessitated replacement with CarboMedics prosthesis. Unfortunately, the patient did not survive. Cunninghamella spp. was confirmed via the PCR analysis of vegetations. Cunninghamella endocarditis in the context of a systemic infection presented as an opportunistic infection affecting a child who had several risk factors. Mucormycosis is challenging to treat, with high mortality. Prophylactic treatment in beta-thalassemia patients with iron-chelator deprivation drugs, such as deferiprone, may help in preventing these particular fungal infections.

A Phase 2a Study Evaluating the Safety and Pharmacokinetics (PK) of Luspatercept in Pediatric Patients with Transfusion-Dependent β-Thalassemia (TDT)

Background: β-thalassemia is an inherited hemoglobinopathy caused by mutations in the gene encoding the β-globin chain of hemoglobin (Hb), resulting in ineffective erythropoiesis, impaired red blood cell (RBC) maturation, and anemia. Patients (pts) with severe disease require regular, lifelong RBC transfusions and iron chelation therapy (ICT) shortly after diagnosis in early childhood. There is an unmet need for safe and effective treatments for pediatric pts to address the underlying pathophysiology of β-thalassemia and reduce the burden of chronic RBC transfusions early to prevent secondary iron overload and associated morbidity. Luspatercept is a first-in-class erythroid maturation agent approved in the USA and EU for the treatment of anemia in adult pts with β-thalassemia who require regular RBC transfusions. In previous studies, treatment with luspatercept resulted in clinically significant reductions in RBC transfusion burden in adults with TDT (phase 3 BELIEVE;Cappellini MD, et al. N Engl J Med 2020;382:1219-1231) and increased Hb levels in adults with non-TDT (phase 2 BEYOND study;Taher AT, et al. HemaSphere 2021;5[Suppl 2];S101). This phase 2a study (NCT04143724, EudraCT 2019-000208-13) will evaluate the safety and PK of luspatercept in pediatric pts with β-thalassemia who require regular RBC transfusions. The results will determine a recommended dose (RD) for each age group. Study Design and Methods: Eligible pts will be 6 to < 18 years of age;diagnosed with β-thalassemia, Hb E/β-thalassemia, or α-thalassemia/β-thalassemia;require ≥ 4 RBC units in the 24 weeks prior to enrollment (with no transfusion-free period ≥ 42 days and with a regular history of transfusions for ≥ 2 years);and have Karnofsky (≥ 16 years of age) or Lansky (< 16 years of age) performance status score ≥ 50 at baseline. Exclusion criteria include: a Hb S/β-thalassemia or α-thalassemia diagnosis, chronic anticoagulant therapy ≤ 28 days prior to enrollment, erythropoiesis-stimulating agent or hydroxyurea use ≤ 24 weeks prior to enrollment, ICT initiation ≤ 8 weeks prior to enrollment, use of any investigational drug ≤ 28 days prior to enrollment, or have undergone or are scheduled for transplant or gene therapy. A total of 54 pts will be enrolled in a staggered study design by age, beginning with a 12-week screening/run-in period. During Part A, pts 12 to < 18 years of age will receive luspatercept at 0.75 mg/kg (n = 6;Cohort 1) or 1.0 mg/kg (n = 6;Cohort 2) subcutaneously (s.c.) once every 21 days for ≤ 4 cycles (Figure A). The RD will be determined for each age group strata at the time of enrollment using descriptive statistics or frequency tabulations between and in aggregate across age-group arms. An expansion cohort (n = 30 pts 12 to < 18 years of age;Cohort 3) will then receive luspatercept for at least 1 year at the RD based on tolerability and safety data from Cohorts 1 and 2;if the RD is 1 mg/kg, titration up to 1.25 mg/kg is allowed in the expansion cohort based on erythroid response during the previous 2 dose cycles. Part B will be initiated following completion of Part A and review of overall safety data with the Data Monitoring Committee, Scientific Steering Committee, and health authorities. Pts 6 to < 12 years of age will be treated with luspatercept at 1.0 mg/kg (n = 6;Cohort 4) or 1.25 mg/kg (n = 6;Cohort 5) s.c. once every 21 days for ≤ 4 cycles (Figure B). Any pt who benefits from treatment can continue to receive luspatercept for ≤ 5 years from first dose and will be monitored for 5 years from first dose or 3 years from last dose, whichever occurs later. Pts may receive best supportive care, including RBC transfusions, ICT, antibiotics, antifungal or antiviral therapy, and/or nutritional support, as needed. The primary objectives are to determine the RD of luspatercept that is safe and tolerable and the PK of luspatercept in pediatric pts with TDT. Key secondary objectives include evaluating mean change in RBC transfusion burden, change in Hb levels, mean change in daily dose of ICT, mean change in serum ferritin, and the immunogenicity and safety of luspatercept in pediatric pts. Safety endpoints include evaluating the type, frequency, seriousness, and severity of adverse events and their relationship to luspatercept treatment. Exploratory endpoints include evaluating exposure-response, health-related quality of life, biomarkers/markers of iron overload and ineffective erythropoiesis, and SARS-CoV-2 serology. [Formula presented] Disclosures: Viprakasit: Bristol Myers Squibb: Research Funding. Coates: Celgene: Consultancy, Honoraria, Research Funding;Forma Pharma: Consultancy;Sangamo: Consultancy;UpToDate: Patents & Royalties;Vifor Pharma: Consultancy;Apo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees;Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees;Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Chiesi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Musallam: Celgene, Bristol Myers Squibb: Consultancy;Novartis: Consultancy;Agios Pharmaceuticals: Consultancy;CRISPR Therapeutics: Consultancy;Vifor Pharma: Consultancy. Vienne Buerki: Bristol Myers Squibb: Current Employment. Patturajan: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Holot: Bristol Myers Squibb: Current Employment. Aydinok: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Bristol Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding;Resonance Health: Research Funding;CRISPR Therapeutics: Consultancy;SLN Therapeutics: Consultancy;Imara: Research Funding;Protagonist: Membership on an entity's Board of Directors or advisory committees, Research Funding;Ionis Pharmaceuticals: Research Funding;La Jolla: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Adverse Events Following COVID-19 Vaccination in Transfusion-Dependent -Thalassemia Patients

Introduction: Patients with transfusion-dependent-thalassemia (TDT) are considered as increased risk population for severe and/or morbid COVID-19 infection. Timely vaccination is the main preventive method for severe COVID-19. Different adverse events and reactions following vaccination have been reported, with severe ones being extremely rare. TDT patients may have altered immunity due to chronic transfusions, iron overload and chelation therapy, and splenic dysfunction. The safety profile of vaccination in chronically transfused patients with thalassemia has not been reported. AIM: To evaluate the safety profile of COVID-19 vaccines in TDT patients. Patients and Methods: This is a single institution's, retrospective analysis evaluating all TDT patients, older than 18 years old, who had completed the vaccination protocol at least 30 days before data cut-off time (July 20 th 2021). Adverse events were reported by patients up to 30 days post each dose. Demographic data and hematological data, including mean hemoglobin levels before and up to 30 days after each dose, were recorded. T-test was performed to investigate changes in hematological profile and transfusion burden post vaccination. Results: 186 patients (median age:45;range:18-61 years old;male/female:87/99) were included for data analysis corresponding to 53% of all TDT patients followed in our Thalassemia Unit. Distribution of vaccine types were: Comirnaty -BNT162b2 (Pfizer Inc. and BioNTech)90.86% (n =168), Vaxzevria (previously COVID-19 vaccine, AstraZeneca)1.61% (n=3), Moderna (Moderna TX Inc.)6.99% (n =13) and JNJ-78436735 (Janssen Pharmaceuticals Companies of Johnson & Johnson)0.54% (n =2). No patients had confirmed or suspected previous COVID-19 infection. Adverse events were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The incidence of adverse events after 1 st and 2 nd dose were 43.5% (81/186) and 54.8% (102/186), respectively. Adverse events after 1 st dose included pain at injection site 26.3%( n=49), fatigue 9.7%(n=18), fever 5.4% (n=10),headaches 4.3% (n=8), arthralgia and myalgia 2.2% (n=4), and lymphadenopathy 0.5% (n=1). Adverse events after 2 nd dose included fever 28.5% (n=53), fatigue 17.7% (n=33), pain at injection site 15.6%(n=29), arthralgia and myalgia 11.3% (n=21), headaches 9.1% (n=17), lymphadenopathy 3.2% (n=6), dizziness 0,5% (n=1), tachycardia 0.5% (n=1), diarrhea/ vomiting 0.05% (n=1) and amaurosis fugax 0.5%: (n=1). No grade 4-5 events or anaphylaxis were observed. Two patients (both males, 51 years and 45 years old, respectively) presented with acute hemolytic crisis with hemoglobinuria in 3 rd and 20 th day after the second dose with Pfizer/BioNTech, respectively. They are receiving treatment with corticosteroids without partial response. Both patients had a history of acute hemolysis crisis within the last 3 years. A decrease in Hb levels after either the first or second dose compared to pre-vaccination mean Hb levels was observed (mean=9.9 /sd=0.63 vs mean=9.44 /sd=0.76), (p < 0.001). Conclusions: Compared to the vaccine trials, we observed some lower incidence of vaccine-related adverse events in our cohort of TDT patients, which may be related to the less stringent reporting methods outside official trials. A temporary drop in hemoglobin levels may be noted in chronically transfusion patients, which parallels what is observed when patients are developing infection or inflammation. Of interest, two patients with previous history of alloimmunization, developed hemolysis. Close hematological follow up may be required in TDT patients post vaccination. The risk/benefit of the vaccination is strongly positive for this vulnerable population. Disclosures: Kattamis: Agios Pharmaceuticals: Consultancy;IONIS: Consultancy;VIFOR: Consultancy;CRISPR/Vertex: Consultancy, Honoraria;BMS/Celgene: Consultancy, Honoraria, Research Funding;Chiesi: Honoraria;Novartis: Consultancy, Honoraria, Research Funding;Amgen: Consultancy.

Hepatic Failure in COVID-19: Is Iron Overload the Dangerous Trigger?

Liver injury in COVID-19 patients has progressively emerged, even in those without a history of liver disease, yet the mechanism of liver pathogenicity is still controversial. COVID-19 is frequently associated with increased serum ferritin levels, and hyperferritinemia was shown to correlate with illness severity. The liver is the major site for iron storage, and conditions of iron overload have been established to have a pathogenic role in development of liver diseases. We presented here six patients who developed severe COVID-19, with biochemical evidence of liver failure. Three cases were survived patients, who underwent liver biopsy; the other three were deceased patients, who were autopsied. None of the patients suffered underlying liver pathologies. Histopathological and ultrastructural analyses were performed. The most striking finding we demonstrated in all patients was iron accumulation into hepatocytes, associated with degenerative changes. Abundant ferritin particles were found enclosed in siderosomes, and large aggregates of hemosiderin were found, often in close contact with damaged mitochondria. Iron-caused oxidative stress may be responsible for mitochondria metabolic dysfunction. In agreement with this, association between mitochondria and lipid droplets was also found. Overall, our data suggest that hepatic iron overload could be the pathogenic trigger of liver injury associated to COVID-19.

Role of iron and iron-related proteins in mesenchymal stem cells: Cellular and clinical aspects.

Mesenchymal stem cells (MSCs) are located in various tissues where these cells show niche-dependent multilineage differentiation and secrete immunomodulatory molecules to support numerous physiological processes. Due to their regenerative and reparative properties, MSCs are extremely valuable for cell-based therapy in tackling several pathological conditions including COVID-19. Iron is essential for MSC processes but iron-loading, which is common in several chronic conditions, hinders normal MSC functionality. This not only aggravates disease pathology but can also affect allogeneic and autologous MSC therapy. Thus, understanding MSCs from an iron perspective is of clinical significance. Accordingly, this review highlights the roles of iron and iron-related proteins in MSC physiology. It describes the contribution of iron and endogenous iron-related effectors like hepcidin, ferroportin, transferrin receptor, lactoferrin, lipocalin-2, bone morphogenetic proteins and hypoxia inducible factors in MSC biology. It summarises the excess-iron-induced alterations in MSC components, processes and discusses signalling pathways involving ROS, PI3K/AKT, MAPK, p53, AMPK/MFF/DRP1 and Wnt. Additionally, it evaluates the endogenous and exogenous saviours of MSCs against iron-toxicity. Lastly, it elaborates on the involvement of MSCs in the pathology of clinical conditions of iron-excess, namely, hereditary hemochromatosis, diabetes, ß-thalassaemia and myelodysplastic syndromes. This unique review integrates the distinct fields of iron regulation and MSC physiology. Through an iron-perspective, it describes both mechanistic and clinical aspects of MSCs and proposes an iron-linked MSC-contribution to physiology, pathology and therapeutics. It advances the understanding of MSC biology and may aid in identifying signalling pathways, molecular targets and compounds for formulating adjunctive iron-based therapies for excess-iron conditions, and thereby inform regenerative medicine.

Automated Red Cell Exchange in the Management of Sickle Cell Disease.

Red cell transfusion represents one of the cornerstones of the chronic management of sickle cell disease, as well as its acute complications. Automated red cell exchange can rapidly lower the number of circulating sickle erythrocytes, without causing iron overload. Here, we describe our experience, having offered this intervention since 2011. A transient reduction in the platelet count by 61% was observed after the procedure. This was not associated with any haemorrhagic complications. Despite exposure to large volumes of blood, the alloimmunisation rate was only 0.027/100 units of red cells. The absence of any iron loading was confirmed by serial Ferriscans, performed over a number of years. However, patients with advanced chronic kidney disease showed evidence of iron loading due to reduced innate haemopoiesis and were subsequently switched to simple transfusions. A total of 59% of patients were on regular automated red cell exchange with a history of recurrent painful crises. A total of 77% responded clinically, as evidenced by at least a 25% reduction in their emergency hospital attendance for pain management. The clinical response was gradual and increased the longer patients stayed on the program. The earliest sign of clinical response was a reduction in the length of stay when these patients were hospitalised, indicating that a reduction in the severity of crises precedes the reduction in their frequency. Automated red cell exchange also appeared to be beneficial for patients with recurrent leg ulcers and severe, drug resistant stuttering priapism, while patients with pulmonary hypertension showed a dramatic improvement in their symptoms as well as echocardiographic parameters.

The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators.

Iron overload is increasingly implicated as a contributor to the pathogenesis of COVID-19. Indeed, several of the manifestations of COVID-19, such as inflammation, hypercoagulation, hyperferritinemia, and immune dysfunction are also reminiscent of iron overload. Although iron is essential for all living cells, free unbound iron, resulting from iron dysregulation and overload, is very reactive and potentially toxic due to its role in the generation of reactive oxygen species (ROS). ROS react with and damage cellular lipids, nucleic acids, and proteins, with consequent activation of either acute or chronic inflammatory processes implicated in multiple clinical conditions. Moreover, iron-catalyzed lipid damage exerts a direct causative effect on the newly discovered nonapoptotic cell death known as ferroptosis. Unlike apoptosis, ferroptosis is immunogenic and not only leads to amplified cell death but also promotes a series of reactions associated with inflammation. Iron chelators are generally safe and are proven to protect patients in clinical conditions characterized by iron overload. There is also an abundance of evidence that iron chelators possess antiviral activities. Furthermore, the naturally occurring iron chelator lactoferrin (Lf) exerts immunomodulatory as well as anti-inflammatory effects and can bind to several receptors used by coronaviruses thereby blocking their entry into host cells. Iron chelators may consequently be of high therapeutic value during the present COVID-19 pandemic.