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      COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy

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          Abstract

          SARS-CoV-2 infection is characterized by a protean clinical picture that can range from asymptomatic patients to life-threatening conditions. Severe COVID-19 patients often display a severe pulmonary involvement and develop neutrophilia, lymphopenia, and strikingly elevated levels of IL-6. There is an over-exuberant cytokine release with hyperferritinemia leading to the idea that COVID-19 is part of the hyperferritinemic syndrome spectrum. Indeed, very high levels of ferritin can occur in other diseases including hemophagocytic lymphohistiocytosis, macrophage activation syndrome, adult-onset Still’s disease, catastrophic antiphospholipid syndrome and septic shock. Numerous studies have demonstrated the immunomodulatory effects of ferritin and its association with mortality and sustained inflammatory process. High levels of free iron are harmful in tissues, especially through the redox damage that can lead to fibrosis. Iron chelation represents a pillar in the treatment of iron overload. In addition, it was proven to have an anti-viral and anti-fibrotic activity. Herein, we analyse the pathogenic role of ferritin and iron during SARS-CoV-2 infection and propose iron depletion therapy as a novel therapeutic approach in the COVID-19 pandemic.

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          Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

          Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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            A pneumonia outbreak associated with a new coronavirus of probable bat origin

            Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.
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              COVID-19: consider cytokine storm syndromes and immunosuppression

              As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. 2 Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections 3 and occurs in 3·7–4·3% of sepsis cases. 4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. 5 A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α. 6 Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p 39·4°C 49 Organomegaly None 0 Hepatomegaly or splenomegaly 23 Hepatomegaly and splenomegaly 38 Number of cytopenias * One lineage 0 Two lineages 24 Three lineages 34 Triglycerides (mmol/L) 4·0 mmol/L 64 Fibrinogen (g/L) >2·5 g/L 0 ≤2·5 g/L 30 Ferritin ng/ml 6000 ng/ml 50 Serum aspartate aminotransferase <30 IU/L 0 ≥30 IU/L 19 Haemophagocytosis on bone marrow aspirate No 0 Yes 35 Known immunosuppression † No 0 Yes 18 The Hscore 11 generates a probability for the presence of secondary HLH. HScores greater than 169 are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores can be calculated using an online HScore calculator. 11 HLH=haemophagocytic lymphohistiocytosis. * Defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm3 or less, or platelet count of 110 000 platelets per mm3 or less, or all of these criteria combined. † HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).
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                Author and article information

                Contributors
                roberto.gerli@unipg.it
                Journal
                Immunol Res
                Immunol. Res
                Immunologic Research
                Springer US (New York )
                0257-277X
                1559-0755
                17 July 2020
                17 July 2020
                : 1-12
                Affiliations
                [1 ]GRID grid.9027.c, ISNI 0000 0004 1757 3630, Rheumatology, Department of Medicine, , University of Perugia, ; Piazzale Giorgio Menghini, 1, 06129 Perugia, Italy
                [2 ]GRID grid.417728.f, ISNI 0000 0004 1756 8807, Rheumatology and Clinical Immunology Humanitas Research Hospital, ; Rozzano, Milan, Italy
                [3 ]GRID grid.12136.37, ISNI 0000 0004 1937 0546, Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, , Tel-Aviv University, ; 5265601 Tel-Hashomer, Israel
                [4 ]GRID grid.15447.33, ISNI 0000 0001 2289 6897, The Mosaic of Autoimmunity Project, , Saint Petersburg University, ; Saint Petersburg, Russia
                [5 ]GRID grid.448878.f, ISNI 0000 0001 2288 8774, Ministry of Health of the Russian Federation, , Sechenov First Moscow State Medical University, ; Moscow, Russia
                Author information
                http://orcid.org/0000-0003-4771-6981
                Article
                9145
                10.1007/s12026-020-09145-5
                7366458
                32681497
                67ff70ae-383e-4ca7-b816-6d1a20aa8edc
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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                Funding
                Funded by: Università degli Studi di Perugia
                Categories
                Interpretive Synthesis Review Article

                sars-cov-2,covid-19,anti-viral,iron,hyperferritinemic,hemophagocytic lymphohistiocytosis,macrophage activation syndrome,adult-onset still’s disease,catastrophic antiphospholipid syndrome,deferoxamine,iron depletion therapy

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