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Lessons Learned Comparing Immune System Alterations of Bacterial Sepsis and SARS-CoV-2 Sepsis. Frontiers in immunology Background:Bacterial sepsis has been used as a prototype to understand the pathogenesis of severe coronavirus disease 2019 (COVID-19). In addition, some management programs for critically ill COVID-19 patients are also based on experience with bacterial sepsis. However, some differences may exist between these two types of sepsis. Methods:This retrospective study investigated whether there are differences in the immune system status of these two types of sepsis. A total of 64 bacterial sepsis patients and 43 patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sepsis were included in this study. Demographic data were obtained from medical records. Laboratory results within 24 h after the diagnosis of sepsis were provided by the clinical laboratory. Results:The results of blood routine (neutrophil, lymphocyte, and monocyte counts), infection biomarkers (C-reactive protein, ferritin, and procalcitonin levels), lymphocyte subset counts (total T lymphocyte, CD4+ T cell, CD8+ T cell, B cell, and NK cell counts), and lymphocyte subset functions (the proportions of PMA/ionomycin-stimulated IFN-γ positive cells in CD4+, CD8+ T cells, and NK cells) were similar in bacterial sepsis patients and SARS-CoV-2 sepsis patients. Cytokine storm was milder, and immunoglobulin and complement protein levels were higher in SARS-CoV-2 sepsis patients. Conclusions:There are both similarities and differences in the immune system status of bacterial sepsis and SARS-CoV-2 sepsis. Our findings do not support blocking the cytokine storm or supplementing immunoglobulins in SARS-CoV-2 sepsis, at least in the early stages of the disease. Treatments for overactivation of the complement system and lymphocyte depletion may be worth exploring further. 10.3389/fimmu.2020.598404
Cardiac dysfunction and ferritin as early markers of severity in pediatric sepsis. Tonial Cristian T,Garcia Pedro Celiny R,Schweitzer Louise Cardoso,Costa Caroline A D,Bruno Francisco,Fiori Humberto H,Einloft Paulo R,Garcia Ricardo Branco,Piva Jefferson Pedro Jornal de pediatria OBJECTIVE:The aim of this study was to verify the association of echocardiogram, ferritin, C-reactive protein, and leukocyte count with unfavorable outcomes in pediatric sepsis. METHODS:A prospective cohort study was carried out from March to December 2014, with pediatric critical care patients aged between 28 days and 18 years. Inclusion criteria were diagnosis of sepsis, need for mechanical ventilation for more than 48h, and vasoactive drugs. Serum levels of C-reactive protein, ferritin, and leukocyte count were collected on the first day (D0), 24h (D1), and 72h (D3) after recruitment. Patients underwent transthoracic echocardiography to determine the ejection fraction of the left ventricle on D1 and D3. The outcomes measured were length of hospital stay and in the pediatric intensive care unit, mechanical ventilation duration, free hours of VM, duration of use of inotropic agents, maximum inotropic score, and mortality. RESULTS:Twenty patients completed the study. Patients with elevated ferritin levels on D0 had also fewer ventilator-free hours (p=0.046) and higher maximum inotropic score (p=0.009). Patients with cardiac dysfunction by echocardiogram on D1 had longer hospital stay (p=0.047), pediatric intensive care unit stay (p=0.020), duration of mechanical ventilation (p=0.011), maximum inotropic score (p=0.001), and fewer ventilator-free hours (p=0.020). CONCLUSION:Cardiac dysfunction by echocardiography and serum ferritin value was significantly associated with unfavorable outcomes in pediatric patients with sepsis. 10.1016/j.jped.2016.08.006
Iron Overload, Oxidative Stress, and Ferroptosis in the Failing Heart and Liver. Mancardi Daniele,Mezzanotte Mariarosa,Arrigo Elisa,Barinotti Alice,Roetto Antonella Antioxidants (Basel, Switzerland) Iron accumulation is a key mediator of several cytotoxic mechanisms leading to the impairment of redox homeostasis and cellular death. Iron overload is often associated with haematological diseases which require regular blood transfusion/phlebotomy, and it represents a common complication in thalassaemic patients. Major damages predominantly occur in the liver and the heart, leading to a specific form of cell death recently named ferroptosis. Different from apoptosis, necrosis, and autophagy, ferroptosis is strictly dependent on iron and reactive oxygen species, with a dysregulation of mitochondrial structure/function. Susceptibility to ferroptosis is dependent on intracellular antioxidant capacity and varies according to the different cell types. Chemotherapy-induced cardiotoxicity has been proven to be mediated predominantly by iron accumulation and ferroptosis, whereas there is evidence about the role of ferritin in protecting cardiomyocytes from ferroptosis and consequent heart failure. Another paradigmatic organ for transfusion-associated complication due to iron overload is the liver, in which the role of ferroptosis is yet to be elucidated. Some studies report a role of ferroptosis in the initiation of hepatic inflammation processes while others provide evidence about an involvement in several pathologies including immune-related hepatitis and acute liver failure. In this manuscript, we aim to review the literature to address putative common features between the response to ferroptosis in the heart and liver. A better comprehension of (dys)similarities is pivotal for the development of future therapeutic strategies that can be designed to specifically target this type of cell death in an attempt to minimize iron-overload effects in specific organs. 10.3390/antiox10121864
Transferrin and transferrin receptors update. Kawabata Hiroshi Free radical biology & medicine In vertebrates, transferrin (Tf) safely delivers iron through circulation to cells. Tf-bound iron is incorporated through Tf receptor (TfR) 1-mediated endocytosis. TfR1 can mediate cellular uptake of both Tf and H-ferritin, an iron storage protein. New World arenaviruses, which cause hemorrhagic fever, and Plasmodium vivax use TfR1 for entry into host cells. Human TfR2, another receptor for Tf, is predominantly expressed in hepatocytes and erythroid precursors, and holo-Tf dramatically upregulates its expression. TfR2 forms a complex with hemochromatosis protein, HFE, and serves as a component of the iron sensing machinery in hepatocytes. Defects in TfR2 cause systemic iron overload, hemochromatosis, through down-regulation of hepcidin. In erythroid cells, TfR2 forms a complex with the erythropoietin receptor and regulates erythropoiesis. TfR2 facilitates iron transport from lysosomes to mitochondria in erythroblasts and dopaminergic neurons. Administration of apo-Tf, which scavenges free iron, has been explored for various clinical conditions including atransferrinemia, iron overload, and tissue ischemia. Apo-Tf has also been shown to ameliorate anemia in animal models of β-thalassemia. In this review, I provide an update and summary on our knowledge of mammalian Tf and its receptors. 10.1016/j.freeradbiomed.2018.06.037
Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Dowdle William E,Nyfeler Beat,Nagel Jane,Elling Robert A,Liu Shanming,Triantafellow Ellen,Menon Suchithra,Wang Zuncai,Honda Ayako,Pardee Gwynn,Cantwell John,Luu Catherine,Cornella-Taracido Ivan,Harrington Edmund,Fekkes Peter,Lei Hong,Fang Qing,Digan Mary Ellen,Burdick Debra,Powers Andrew F,Helliwell Stephen B,D'Aquin Simon,Bastien Julie,Wang Henry,Wiederschain Dmitri,Kuerth Jenny,Bergman Philip,Schwalb David,Thomas Jason,Ugwonali Savuth,Harbinski Fred,Tallarico John,Wilson Christopher J,Myer Vic E,Porter Jeffery A,Bussiere Dirksen E,Finan Peter M,Labow Mark A,Mao Xiaohong,Hamann Lawrence G,Manning Brendan D,Valdez Reginald A,Nicholson Thomas,Schirle Markus,Knapp Mark S,Keaney Erin P,Murphy Leon O Nature cell biology Cells rely on autophagy to clear misfolded proteins and damaged organelles to maintain cellular homeostasis. In this study we use the new autophagy inhibitor PIK-III to screen for autophagy substrates. PIK-III is a selective inhibitor of VPS34 that binds a unique hydrophobic pocket not present in related kinases such as PI(3)Kα. PIK-III acutely inhibits autophagy and de novo lipidation of LC3, and leads to the stabilization of autophagy substrates. By performing ubiquitin-affinity proteomics on PIK-III-treated cells we identified substrates including NCOA4, which accumulates in ATG7-deficient cells and co-localizes with autolysosomes. NCOA4 directly binds ferritin heavy chain-1 (FTH1) to target the iron-binding ferritin complex with a relative molecular mass of 450,000 to autolysosomes following starvation or iron depletion. Interestingly, Ncoa4(-/-) mice exhibit a profound accumulation of iron in splenic macrophages, which are critical for the reutilization of iron from engulfed red blood cells. Taken together, the results of this study provide a new mechanism for selective autophagy of ferritin and reveal a previously unappreciated role for autophagy and NCOA4 in the control of iron homeostasis in vivo. 10.1038/ncb3053
Changes in ferrous iron and glutathione promote ferroptosis and frailty in aging . eLife All eukaryotes require iron. Replication, detoxification, and a cancer-protective form of regulated cell death termed , all depend on iron metabolism. Ferrous iron accumulates over adult lifetime in . Here, we show that glutathione depletion is coupled to ferrous iron elevation in these animals, and that both occur in late life to prime cells for ferroptosis. We demonstrate that blocking ferroptosis, either by inhibition of lipid peroxidation or by limiting iron retention, mitigates age-related cell death and markedly increases lifespan and healthspan. Temporal scaling of lifespan is not evident when ferroptosis is inhibited, consistent with this cell death process acting at specific life phases to induce organismal frailty, rather than contributing to a constant aging rate. Because excess age-related iron elevation in somatic tissue, particularly in brain, is thought to contribute to degenerative disease, post-developmental interventions to limit ferroptosis may promote healthy aging. 10.7554/eLife.56580
Combination of inflammatory and vascular markers in the febrile phase of dengue is associated with more severe outcomes. Vuong Nguyen Lam,Lam Phung Khanh,Ming Damien Keng Yen,Duyen Huynh Thi Le,Nguyen Nguyet Minh,Tam Dong Thi Hoai,Duong Thi Hue Kien,Chau Nguyen Vv,Chanpheaktra Ngoun,Lum Lucy Chai See,Pleités Ernesto,Simmons Cameron P,Rosenberger Kerstin D,Jaenisch Thomas,Bell David,Acestor Nathalie,Halleux Christine,Olliaro Piero L,Wills Bridget A,Geskus Ronald B,Yacoub Sophie eLife Background:Early identification of severe dengue patients is important regarding patient management and resource allocation. We investigated the association of 10 biomarkers (VCAM-1, SDC-1, Ang-2, IL-8, IP-10, IL-1RA, sCD163, sTREM-1, ferritin, CRP) with the development of severe/moderate dengue (S/MD). Methods:We performed a nested case-control study from a multi-country study. A total of 281 S/MD and 556 uncomplicated dengue cases were included. Results:On days 1-3 from symptom onset, higher levels of any biomarker increased the risk of developing S/MD. When assessing together, SDC-1 and IL-1RA were stable, while IP-10 changed the association from positive to negative; others showed weaker associations. The best combinations associated with S/MD comprised IL-1RA, Ang-2, IL-8, ferritin, IP-10, and SDC-1 for children, and SDC-1, IL-8, ferritin, sTREM-1, IL-1RA, IP-10, and sCD163 for adults. Conclusions:Our findings assist the development of biomarker panels for clinical use and could improve triage and risk prediction in dengue patients. Funding:This study was supported by the EU's Seventh Framework Programme (FP7-281803 IDAMS), the WHO, and the Bill and Melinda Gates Foundation. 10.7554/eLife.67460
Neurological associations of COVID-19. The Lancet. Neurology BACKGROUND:The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is of a scale not seen since the 1918 influenza pandemic. Although the predominant clinical presentation is with respiratory disease, neurological manifestations are being recognised increasingly. On the basis of knowledge of other coronaviruses, especially those that caused the severe acute respiratory syndrome and Middle East respiratory syndrome epidemics, cases of CNS and peripheral nervous system disease caused by SARS-CoV-2 might be expected to be rare. RECENT DEVELOPMENTS:A growing number of case reports and series describe a wide array of neurological manifestations in 901 patients, but many have insufficient detail, reflecting the challenge of studying such patients. Encephalopathy has been reported for 93 patients in total, including 16 (7%) of 214 hospitalised patients with COVID-19 in Wuhan, China, and 40 (69%) of 58 patients in intensive care with COVID-19 in France. Encephalitis has been described in eight patients to date, and Guillain-Barré syndrome in 19 patients. SARS-CoV-2 has been detected in the CSF of some patients. Anosmia and ageusia are common, and can occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease is also emerging as an important complication, with cohort studies reporting stroke in 2-6% of patients hospitalised with COVID-19. So far, 96 patients with stroke have been described, who frequently had vascular events in the context of a pro-inflammatory hypercoagulable state with elevated C-reactive protein, D-dimer, and ferritin. WHERE NEXT?: Careful clinical, diagnostic, and epidemiological studies are needed to help define the manifestations and burden of neurological disease caused by SARS-CoV-2. Precise case definitions must be used to distinguish non-specific complications of severe disease (eg, hypoxic encephalopathy and critical care neuropathy) from those caused directly or indirectly by the virus, including infectious, para-infectious, and post-infectious encephalitis, hypercoagulable states leading to stroke, and acute neuropathies such as Guillain-Barré syndrome. Recognition of neurological disease associated with SARS-CoV-2 in patients whose respiratory infection is mild or asymptomatic might prove challenging, especially if the primary COVID-19 illness occurred weeks earlier. The proportion of infections leading to neurological disease will probably remain small. However, these patients might be left with severe neurological sequelae. With so many people infected, the overall number of neurological patients, and their associated health burden and social and economic costs might be large. Health-care planners and policy makers must prepare for this eventuality, while the many ongoing studies investigating neurological associations increase our knowledge base. 10.1016/S1474-4422(20)30221-0
Differential protein expression in patients with urosepsis. Chinese journal of traumatology = Zhonghua chuang shang za zhi PURPOSE:Urosepsis in adults comprises approximately 25% of all sepsis cases, and is due to complicated urinary tract infections in most cases. However, its mechanism is not fully clarified. Urosepsis is a very complicated disease with no effective strategy for early diagnosis and treatment. This study aimed to identify possible target-related proteins involved in urosepsis using proteomics and establish possible networks using bioinformatics. METHODS:Fifty patients admitted to the Urology Unit of Lanzhou General PLA (Lanzhou, China), from October 2012 to October 2015, were enrolled in this study. The patients were further divided into shock and matched-pair non-shock groups. 2-DE technique, mass spectrometry and database search were used to detect differentially expressed proteins in serum from the two groups. RESULTS:Six proteins were found at higher levels in the shock group compared with non-shock individuals, including serum amyloid A-1 protein (SAA1), apolipoprotein L1 (APOL1), ceruloplasmin (CP), haptoglobin (HP), antithrombin-III (SERPINC1) and prothrombin (F2), while three proteins showed lower levels, including serotransferrin (TF), transthyretin (TTR) and alpha-2-macroglobulin (A2M). CONCLUSION:Nine proteins were differentially expressed between uroseptic patients (non-shock groups) and severe uroseptic patients (shock groups), compared with non-shock groups, serum SAA1, APOL1,CP, HP, SERPINC1and F2 at higher levels, while TF, TTR and A2M at lower levels in shock groups.these proteins were mainly involved in platelet activation, signaling and aggregation, acute phase protein pathway, lipid homeostasis, and iron ion transport, deserve further research as potential candidates for early diagnosis and treatment. (The conclusion seems too simple and vague, please re-write it. You may focus at what proteins have been expressed and introduce more detail about its significance.). 10.1016/j.cjtee.2018.07.003
Just a Spoonful of Sugar Helps the Tolerance Go Up. Chervonsky Alexander V Cell Survival of deleterious infections depends significantly on how much stress the affected organism can tolerate. In this issue, Weis et al. find that mice can survive sepsis by maintaining normoglycemia through ferritin's capacity to inactivate Fe ions that otherwise induce free radicals impacting gluconeogenesis in the liver. 10.1016/j.cell.2017.05.040
Advances in Ferritin Physiology and Possible Implications in Bacterial Infection. International journal of molecular sciences Due to its advantageous redox properties, iron plays an important role in the metabolism of nearly all life. However, these properties are not only a boon but also the bane of such life forms. Since labile iron results in the generation of reactive oxygen species by Fenton chemistry, iron is stored in a relatively safe form inside of ferritin. Despite the fact that the iron storage protein ferritin has been extensively researched, many of its physiological functions are hitherto unresolved. However, research regarding ferritin's functions is gaining momentum. For example, recent major discoveries on its secretion and distribution mechanisms have been made as well as the paradigm-changing finding of intracellular compartmentalization of ferritin via interaction with nuclear receptor coactivator 4 (NCOA4). In this review, we discuss established knowledge as well as these new findings and the implications they may have for host-pathogen interaction during bacterial infection. 10.3390/ijms24054659
Mitochondrial ferritin. Levi Sonia,Arosio Paolo The international journal of biochemistry & cell biology A novel ferritin type specifically targeted to mitochondria has been recently found in human and mouse. It is structurally and functionally similar to the cytosolic ferritins, well-characterized molecules found in most living systems which are designed to store and detoxify cellular iron. Cytosolic ferritins in mammals are ubiquitous while mitochondrial ferritin expression is restricted mainly to the testis, neuronal cells and islets of Langherans. In addition, it is abundant in the iron-loaded mitochondria of erythroblasts of patients with sideroblastic anaemia. The characterization of recombinant and transfected mitochondrial ferritin indicated that this protein has a role in protecting mitochondria from iron-induced damage. These data suggest that it is an interesting tool to study the iron metabolism in this organelle. In addition, it may be useful for the diagnosis of myelodysplastic syndromes and in protecting mitochondria from the toxic effects of excess iron. 10.1016/j.biocel.2003.10.020
Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Kell Douglas B,Pretorius Etheresia Metallomics : integrated biometal science "Serum ferritin" presents a paradox, as the iron storage protein ferritin is not synthesised in serum yet is to be found there. Serum ferritin is also a well known inflammatory marker, but it is unclear whether serum ferritin reflects or causes inflammation, or whether it is involved in an inflammatory cycle. We argue here that serum ferritin arises from damaged cells, and is thus a marker of cellular damage. The protein in serum ferritin is considered benign, but it has lost (i.e. dumped) most of its normal complement of iron which when unliganded is highly toxic. The facts that serum ferritin levels can correlate with both disease and with body iron stores are thus expected on simple chemical kinetic grounds. Serum ferritin levels also correlate with other phenotypic readouts such as erythrocyte morphology. Overall, this systems approach serves to explain a number of apparent paradoxes of serum ferritin, including (i) why it correlates with biomarkers of cell damage, (ii) why it correlates with biomarkers of hydroxyl radical formation (and oxidative stress) and (iii) therefore why it correlates with the presence and/or severity of numerous diseases. This leads to suggestions for how one might exploit the corollaries of the recognition that serum ferritin levels mainly represent a consequence of cell stress and damage. 10.1039/c3mt00347g
Effects of tuberculosis and/or HIV-1 infection on COVID-19 presentation and immune response in Africa. Nature communications Few studies from Africa have described the clinical impact of co-infections on SARS-CoV-2 infection. Here, we investigate the presentation and outcome of SARS-CoV-2 infection in an African setting of high HIV-1 and tuberculosis prevalence by an observational case cohort of SARS-CoV-2 patients. A comparator group of non SARS-CoV-2 participants is included. The study includes 104 adults with SARS-CoV-2 infection of whom 29.8% are HIV-1 co-infected. Two or more co-morbidities are present in 57.7% of participants, including HIV-1 (30%) and active tuberculosis (14%). Amongst patients dually infected by tuberculosis and SARS-CoV-2, clinical features can be typical of either SARS-CoV-2 or tuberculosis: lymphopenia is exacerbated, and some markers of inflammation (D-dimer and ferritin) are further elevated (p < 0.05). Amongst HIV-1 co-infected participants those with low CD4 percentage strata exhibit reduced total, but not neutralising, anti-SARS-CoV-2 antibodies. SARS-CoV-2 specific CD8 T cell responses are present in 35.8% participants overall but undetectable in combined HIV-1 and tuberculosis. Death occurred in 30/104 (29%) of all COVID-19 patients and in 6/15 (40%) of patients with coincident SARS-CoV-2 and tuberculosis. This shows that in a high incidence setting, tuberculosis is a common co-morbidity in patients admitted to hospital with COVID-19. The immune response to SARS-CoV-2 is adversely affected by co-existent HIV-1 and tuberculosis. 10.1038/s41467-022-35689-1
Elevated plasma ferritin in elderly individuals with high neocortical amyloid-β load. Goozee K,Chatterjee P,James I,Shen K,Sohrabi H R,Asih P R,Dave P,ManYan C,Taddei K,Ayton S J,Garg M L,Kwok J B,Bush A I,Chung R,Magnussen J S,Martins R N Molecular psychiatry Ferritin, an iron storage and regulation protein, has been associated with Alzheimer's disease (AD); however, it has not been investigated in preclinical AD, detected by neocortical amyloid-β load (NAL), before cognitive impairment. Cross-sectional analyses were carried out for plasma and serum ferritin in participants in the Kerr Anglican Retirement Village Initiative in Aging Health cohort. Subjects were aged 65-90 years and were categorized into high and low NAL groups via positron emission tomography using a standard uptake value ratio cutoff=1.35. Ferritin was significantly elevated in participants with high NAL compared with those with low NAL, adjusted for covariates age, sex, apolipoprotein E ɛ4 carriage and levels of C-reactive protein (an inflammation marker). Ferritin was also observed to correlate positively with NAL. A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished high from low NAL (area under the curve (AUC)=0.766), but was outperformed when plasma ferritin was added to the base model (AUC=0.810), such that at 75% sensitivity, the specificity increased from 62 to 71% on adding ferritin to the base model, indicating that ferritin is a statistically significant additional predictor of NAL over and above the base model. However, ferritin's contribution alone is relatively minor compared with the base model. The current findings suggest that impaired iron mobilization is an early event in AD pathogenesis. Observations from the present study highlight ferritin's potential to contribute to a blood biomarker panel for preclinical AD. 10.1038/mp.2017.146
Serum ferritin and risk for new-onset heart failure and cardiovascular events in the community. Klip IJsbrand T,Voors Adriaan A,Swinkels Dorine W,Bakker Stephan J L,Kootstra-Ros Jenny E,Lam Carolyn S,van der Harst Pim,van Veldhuisen Dirk J,van der Meer Peter European journal of heart failure AIMS:Heart failure (HF) is a common manifestation of patients with primary and secondary causes of iron overload, whereas in patients with established HF iron deficiency impairs outcome. Whether iron stores, either depleted or in overload, amplify the risk for new-onset HF among healthy individuals is unknown. The present study aimed to assess whether markers of iron status or the iron-regulatory hormone hepcidin are associated with new-onset HF or cardiovascular (CV) events in the general population. METHODS AND RESULTS:In 6386 subjects from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) trial, a prospective, community-based, cohort study, markers of iron status and the iron-regulatory hormone hepcidin were measured. Mean age was 53.1 ± 12.0 years, and 50.7% of the cohort was female. During a median follow-up of 8.3 (interquartile range 7.8-8.9) years, 199 subjects (3.1%) were newly diagnosed with HF, 456 (7.1%) experienced a CV event, and 356 (5.6%) died from all causes. A higher annual HF incidence per ferritin quartile was observed in women (P < 0.001), but not in men (P for interaction 0.032). Multivariable analyses demonstrated ferritin levels to remain independently predictive for new-onset HF in women only (P = 0.024). This association persisted within strata defined by markers of the metabolic syndrome, markers of inflammation, or other markers of iron homeostasis, including hepcidin. No association between ferritin or hepcidin and incident CV events or all-cause mortality was observed in either sex. CONCLUSIONS:Increased serum ferritin levels independently amplify the risk for new-onset HF in women in the community. 10.1002/ejhf.622
Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2. JAMA Importance:In communities with high rates of coronavirus disease 2019, reports have emerged of children with an unusual syndrome of fever and inflammation. Objectives:To describe the clinical and laboratory characteristics of hospitalized children who met criteria for the pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PIMS-TS) and compare these characteristics with other pediatric inflammatory disorders. Design, Setting, and Participants:Case series of 58 children from 8 hospitals in England admitted between March 23 and May 16, 2020, with persistent fever and laboratory evidence of inflammation meeting published definitions for PIMS-TS. The final date of follow-up was May 22, 2020. Clinical and laboratory characteristics were abstracted by medical record review, and were compared with clinical characteristics of patients with Kawasaki disease (KD) (n = 1132), KD shock syndrome (n = 45), and toxic shock syndrome (n = 37) who had been admitted to hospitals in Europe and the US from 2002 to 2019. Exposures:Signs and symptoms and laboratory and imaging findings of children who met definitional criteria for PIMS-TS from the UK, the US, and World Health Organization. Main Outcomes and Measures:Clinical, laboratory, and imaging characteristics of children meeting definitional criteria for PIMS-TS, and comparison with the characteristics of other pediatric inflammatory disorders. Results:Fifty-eight children (median age, 9 years [interquartile range {IQR}, 5.7-14]; 20 girls [34%]) were identified who met the criteria for PIMS-TS. Results from SARS-CoV-2 polymerase chain reaction tests were positive in 15 of 58 patients (26%) and SARS-CoV-2 IgG test results were positive in 40 of 46 (87%). In total, 45 of 58 patients (78%) had evidence of current or prior SARS-CoV-2 infection. All children presented with fever and nonspecific symptoms, including vomiting (26/58 [45%]), abdominal pain (31/58 [53%]), and diarrhea (30/58 [52%]). Rash was present in 30 of 58 (52%), and conjunctival injection in 26 of 58 (45%) cases. Laboratory evaluation was consistent with marked inflammation, for example, C-reactive protein (229 mg/L [IQR, 156-338], assessed in 58 of 58) and ferritin (610 μg/L [IQR, 359-1280], assessed in 53 of 58). Of the 58 children, 29 developed shock (with biochemical evidence of myocardial dysfunction) and required inotropic support and fluid resuscitation (including 23/29 [79%] who received mechanical ventilation); 13 met the American Heart Association definition of KD, and 23 had fever and inflammation without features of shock or KD. Eight patients (14%) developed coronary artery dilatation or aneurysm. Comparison of PIMS-TS with KD and with KD shock syndrome showed differences in clinical and laboratory features, including older age (median age, 9 years [IQR, 5.7-14] vs 2.7 years [IQR, 1.4-4.7] and 3.8 years [IQR, 0.2-18], respectively), and greater elevation of inflammatory markers such as C-reactive protein (median, 229 mg/L [IQR 156-338] vs 67 mg/L [IQR, 40-150 mg/L] and 193 mg/L [IQR, 83-237], respectively). Conclusions and Relevance:In this case series of hospitalized children who met criteria for PIMS-TS, there was a wide spectrum of presenting signs and symptoms and disease severity, ranging from fever and inflammation to myocardial injury, shock, and development of coronary artery aneurysms. The comparison with patients with KD and KD shock syndrome provides insights into this syndrome, and suggests this disorder differs from other pediatric inflammatory entities. 10.1001/jama.2020.10369
Criteria for Iron Deficiency in Patients With Heart Failure. Masini Gabriele,Graham Fraser J,Pellicori Pierpaolo,Cleland John G F,Cuthbert Joseph J,Kazmi Syed,Inciardi Riccardo M,Clark Andrew L Journal of the American College of Cardiology BACKGROUND:Guidelines on heart failure (HF) define iron deficiency (ID) as a serum ferritin <100 ng/mL or, when 100-299 ng/mL, a transferrin saturation (TSAT) <20%. Inflammation (common in HF) may hinder interpretation of serum ferritin. OBJECTIVES:This study sought to investigate how different definitions of ID affect its prevalence and relationship to prognosis in ambulatory patients with chronic HF. METHODS:Prevalence, relationship with patients' characteristics, and outcomes of various ID definitions were evaluated among patients with HF referred to a regional clinic (Hull LifeLab) from 2001 to 2019. RESULTS:Of 4,422 patients with HF (median age 75 years [range: 68-82 years], 60% men, 32% with reduced left ventricular ejection fraction), 46% had TSAT <20%, 48% had serum iron ≤13 μmol/L, 57% had serum ferritin <100 ng/mL, and 68% fulfilled current guideline criteria for ID, of whom 35% had a TSAT >20%. Irrespective of definition, ID was more common in women and those with more severe symptoms, anemia, or preserved ejection fraction. TSAT <20% and serum iron ≤13 μmol/L, but not guideline criteria, were associated with higher 5-year mortality (HR: 1.27; 95% CI: 1.14-1.43; P < 0.001; and HR: 1.37; 95% CI: 1.22-1.54; P < 0.001, respectively). Serum ferritin <100 ng/mL tended to be associated with lower mortality (HR: 0.91; 95% CI: 0.81-1.01; P = 0.09). CONCLUSIONS:Different definitions of ID provide discordant results for prevalence and prognosis. Definitions lacking specificity may attenuate the benefits of intravenous iron observed in trials while definitions lacking sensitivity may exclude patients who should receive intravenous iron. Prespecified subgroup analyses of ongoing randomized trials should address this issue. 10.1016/j.jacc.2021.11.039
Electron Transfer from Haem to the Di-Iron Ferroxidase Centre in Bacterioferritin. Pullin Jacob,Bradley Justin M,Moore Geoffrey R,Le Brun Nick E,Wilson Michael T,Svistunenko Dimitri A Angewandte Chemie (International ed. in English) The iron redox cycle in ferritins is not completely understood. Bacterioferritins are distinct from other ferritins in that they contain haem groups. It is acknowledged that the two iron motifs in bacterioferritins, the di-nuclear ferroxidase centre and the haem B group, play key roles in two opposing processes, iron sequestration and iron mobilisation, respectively, and the two redox processes are independent. Herein, we show that in Escherichia coli bacterioferritin, there is an electron transfer pathway from the haem to the ferroxidase centre suggesting a new role(s) haem might play in bacterioferritins. 10.1002/anie.202015965
Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure. Haddad Saba,Wang Yong,Galy Bruno,Korf-Klingebiel Mortimer,Hirsch Valentin,Baru Abdul M,Rostami Fatemeh,Reboll Marc R,Heineke Jörg,Flögel Ulrich,Groos Stephanie,Renner André,Toischer Karl,Zimmermann Fabian,Engeli Stefan,Jordan Jens,Bauersachs Johann,Hentze Matthias W,Wollert Kai C,Kempf Tibor European heart journal Aims:Iron deficiency (ID) is associated with adverse outcomes in heart failure (HF) but the underlying mechanisms are incompletely understood. Intracellular iron availability is secured by two mRNA-binding iron-regulatory proteins (IRPs), IRP1 and IRP2. We generated mice with a cardiomyocyte-targeted deletion of Irp1 and Irp2 to explore the functional implications of ID in the heart independent of systemic ID and anaemia. Methods and results:Iron content in cardiomyocytes was reduced in Irp-targeted mice. The animals were not anaemic and did not show a phenotype under baseline conditions. Irp-targeted mice, however, were unable to increase left ventricular (LV) systolic function in response to an acute dobutamine challenge. After myocardial infarction, Irp-targeted mice developed more severe LV dysfunction with increased HF mortality. Mechanistically, the activity of the iron-sulphur cluster-containing complex I of the mitochondrial electron transport chain was reduced in left ventricles from Irp-targeted mice. As demonstrated by extracellular flux analysis in vitro, mitochondrial respiration was preserved at baseline but failed to increase in response to dobutamine in Irp-targeted cardiomyocytes. As shown by 31P-magnetic resonance spectroscopy in vivo, LV phosphocreatine/ATP ratio declined during dobutamine stress in Irp-targeted mice but remained stable in control mice. Intravenous injection of ferric carboxymaltose replenished cardiac iron stores, restored mitochondrial respiratory capacity and inotropic reserve, and attenuated adverse remodelling after myocardial infarction in Irp-targeted mice but not in control mice. As shown by electrophoretic mobility shift assays, IRP activity was significantly reduced in LV tissue samples from patients with advanced HF and reduced LV tissue iron content. Conclusions:ID in cardiomyocytes impairs mitochondrial respiration and adaptation to acute and chronic increases in workload. Iron supplementation restores cardiac energy reserve and function in iron-deficient hearts. 10.1093/eurheartj/ehw333
Enzyme Encapsulation by a Ferritin Cage. Tetter Stephan,Hilvert Donald Angewandte Chemie (International ed. in English) Ferritins, conserved across all kingdoms of life, are protein nanocages that evolved to mineralize iron. The last several decades have shown that these cages have considerable technological and medical potential owing to their stability and tolerance to modification, as well as their ability to template nanoparticle synthesis and incorporate small molecules. Here we show that it is possible to encapsulate proteins in a ferritin cage by exploiting electrostatic interactions with its negatively charged interior. Positively supercharged green fluorescent protein is efficiently taken up by Archaeoglobus fulgidus ferritin in a tunable fashion. Moreover, several enzymes were readily incorporated when genetically tethered to this fluorescent protein. These fusion proteins retained high catalytic activity and showed increased tolerance to proteolysis and heat. Equipping ferritins with enzymatic activity paves the way for many new nanotechnological and pharmacological applications. 10.1002/anie.201708530
PCBP1 and NCOA4 regulate erythroid iron storage and heme biosynthesis. Ryu Moon-Suhn,Zhang Deliang,Protchenko Olga,Shakoury-Elizeh Minoo,Philpott Caroline C The Journal of clinical investigation Developing erythrocytes take up exceptionally large amounts of iron, which must be transferred to mitochondria for incorporation into heme. This massive iron flux must be precisely controlled to permit the coordinated synthesis of heme and hemoglobin while avoiding the toxic effects of chemically reactive iron. In cultured animal cells, iron chaperones poly rC-binding protein 1 (PCBP1) and PCBP2 deliver iron to ferritin, the sole cytosolic iron storage protein, and nuclear receptor coactivator 4 (NCOA4) mediates the autophagic turnover of ferritin. The roles of PCBP, ferritin, and NCOA4 in erythroid development remain unclear. Here, we show that PCBP1, NCOA4, and ferritin are critical for murine red cell development. Using a cultured cell model of erythroid differentiation, depletion of PCBP1 or NCOA4 impaired iron trafficking through ferritin, which resulted in reduced heme synthesis, reduced hemoglobin formation, and perturbation of erythroid regulatory systems. Mice lacking Pcbp1 exhibited microcytic anemia and activation of compensatory erythropoiesis via the regulators erythropoietin and erythroferrone. Ex vivo differentiation of erythroid precursors from Pcbp1-deficient mice confirmed defects in ferritin iron flux and heme synthesis. These studies demonstrate the importance of ferritin for the vectorial transfer of imported iron to mitochondria in developing red cells and of PCBP1 and NCOA4 in mediating iron flux through ferritin. 10.1172/JCI90519
Ferritin is secreted via 2 distinct nonclassical vesicular pathways. Truman-Rosentsvit Marianna,Berenbaum Dina,Spektor Lior,Cohen Lyora A,Belizowsky-Moshe Shirly,Lifshitz Lena,Ma Jing,Li Wei,Kesselman Ellina,Abutbul-Ionita Inbal,Danino Dganit,Gutierrez Lucia,Li Huihui,Li Kuanyu,Lou Huifang,Regoni Maria,Poli Maura,Glaser Fabian,Rouault Tracey A,Meyron-Holtz Esther G Blood Ferritin turnover plays a major role in tissue iron homeostasis, and ferritin malfunction is associated with impaired iron homeostasis and neurodegenerative diseases. In most eukaryotes, ferritin is considered an intracellular protein that stores iron in a nontoxic and bioavailable form. In insects, ferritin is a classically secreted protein and plays a major role in systemic iron distribution. Mammalian ferritin lacks the signal peptide for classical endoplasmic reticulum-Golgi secretion but is found in serum and is secreted via a nonclassical lysosomal secretion pathway. This study applied bioinformatics and biochemical tools, alongside a protein trafficking mouse models, to characterize the mechanisms of ferritin secretion. Ferritin trafficking via the classical secretion pathway was ruled out, and a 2:1 distribution of intracellular ferritin between membrane-bound compartments and the cytosol was observed, suggesting a role for ferritin in the vesicular compartments of the cell. Focusing on nonclassical secretion, we analyzed mouse models of impaired endolysosomal trafficking and found that ferritin secretion was decreased by a BLOC-1 mutation but increased by BLOC-2, BLOC-3, and Rab27A mutations of the cellular trafficking machinery, suggesting multiple export routes. A 13-amino-acid motif unique to ferritins that lack the secretion signal peptide was identified on the BC-loop of both subunits and plays a role in the regulation of ferritin secretion. Finally, we provide evidence that secretion of iron-rich ferritin was mediated via the multivesicular body-exosome pathway. These results enhance our understanding of the mechanism of ferritin secretion, which is an important piece in the puzzle of tissue iron homeostasis. 10.1182/blood-2017-02-768580
Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-AID): a factorial, randomised, controlled trial. Declercq Jozefien,Van Damme Karel F A,De Leeuw Elisabeth,Maes Bastiaan,Bosteels Cedric,Tavernier Simon J,De Buyser Stefanie,Colman Roos,Hites Maya,Verschelden Gil,Fivez Tom,Moerman Filip,Demedts Ingel K,Dauby Nicolas,De Schryver Nicolas,Govaerts Elke,Vandecasteele Stefaan J,Van Laethem Johan,Anguille Sebastien,van der Hilst Jeroen,Misset Benoit,Slabbynck Hans,Wittebole Xavier,Liénart Fabienne,Legrand Catherine,Buyse Marc,Stevens Dieter,Bauters Fre,Seys Leen J M,Aegerter Helena,Smole Ursula,Bosteels Victor,Hoste Levi,Naesens Leslie,Haerynck Filomeen,Vandekerckhove Linos,Depuydt Pieter,van Braeckel Eva,Rottey Sylvie,Peene Isabelle,Van Der Straeten Catherine,Hulstaert Frank,Lambrecht Bart N The Lancet. Respiratory medicine BACKGROUND:Infections with SARS-CoV-2 continue to cause significant morbidity and mortality. Interleukin (IL)-1 and IL-6 blockade have been proposed as therapeutic strategies in COVID-19, but study outcomes have been conflicting. We sought to study whether blockade of the IL-6 or IL-1 pathway shortened the time to clinical improvement in patients with COVID-19, hypoxic respiratory failure, and signs of systemic cytokine release syndrome. METHODS:We did a prospective, multicentre, open-label, randomised, controlled trial, in hospitalised patients with COVID-19, hypoxia, and signs of a cytokine release syndrome across 16 hospitals in Belgium. Eligible patients had a proven diagnosis of COVID-19 with symptoms between 6 and 16 days, a ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO:FiO) of less than 350 mm Hg on room air or less than 280 mm Hg on supplemental oxygen, and signs of a cytokine release syndrome in their serum (either a single ferritin measurement of more than 2000 μg/L and immediately requiring high flow oxygen or mechanical ventilation, or a ferritin concentration of more than 1000 μg/L, which had been increasing over the previous 24 h, or lymphopenia below 800/mL with two of the following criteria: an increasing ferritin concentration of more than 700 μg/L, an increasing lactate dehydrogenase concentration of more than 300 international units per L, an increasing C-reactive protein concentration of more than 70 mg/L, or an increasing D-dimers concentration of more than 1000 ng/mL). The COV-AID trial has a 2 × 2 factorial design to evaluate IL-1 blockade versus no IL-1 blockade and IL-6 blockade versus no IL-6 blockade. Patients were randomly assigned by means of permuted block randomisation with varying block size and stratification by centre. In a first randomisation, patients were assigned to receive subcutaneous anakinra once daily (100 mg) for 28 days or until discharge, or to receive no IL-1 blockade (1:2). In a second randomisation step, patients were allocated to receive a single dose of siltuximab (11 mg/kg) intravenously, or a single dose of tocilizumab (8 mg/kg) intravenously, or to receive no IL-6 blockade (1:1:1). The primary outcome was the time to clinical improvement, defined as time from randomisation to an increase of at least two points on a 6-category ordinal scale or to discharge from hospital alive. The primary and supportive efficacy endpoints were assessed in the intention-to-treat population. Safety was assessed in the safety population. This study is registered online with ClinicalTrials.gov (NCT04330638) and EudraCT (2020-001500-41) and is complete. FINDINGS:Between April 4, and Dec 6, 2020, 342 patients were randomly assigned to IL-1 blockade (n=112) or no IL-1 blockade (n=230) and simultaneously randomly assigned to IL-6 blockade (n=227; 114 for tocilizumab and 113 for siltuximab) or no IL-6 blockade (n=115). Most patients were male (265 [77%] of 342), median age was 65 years (IQR 54-73), and median Systematic Organ Failure Assessment (SOFA) score at randomisation was 3 (2-4). All 342 patients were included in the primary intention-to-treat analysis. The estimated median time to clinical improvement was 12 days (95% CI 10-16) in the IL-1 blockade group versus 12 days (10-15) in the no IL-1 blockade group (hazard ratio [HR] 0·94 [95% CI 0·73-1·21]). For the IL-6 blockade group, the estimated median time to clinical improvement was 11 days (95% CI 10-16) versus 12 days (11-16) in the no IL-6 blockade group (HR 1·00 [0·78-1·29]). 55 patients died during the study, but no evidence for differences in mortality between treatment groups was found. The incidence of serious adverse events and serious infections was similar across study groups. INTERPRETATION:Drugs targeting IL-1 or IL-6 did not shorten the time to clinical improvement in this sample of patients with COVID-19, hypoxic respiratory failure, low SOFA score, and low baseline mortality risk. FUNDING:Belgian Health Care Knowledge Center and VIB Grand Challenges program. 10.1016/S2213-2600(21)00377-5
Seizure-mediated iron accumulation and dysregulated iron metabolism after status epilepticus and in temporal lobe epilepsy. Zimmer Till S,David Bastian,Broekaart Diede W M,Schidlowski Martin,Ruffolo Gabriele,Korotkov Anatoly,van der Wel Nicole N,van Rijen Peter C,Mühlebner Angelika,van Hecke Wim,Baayen Johannes C,Idema Sander,François Liesbeth,van Eyll Jonathan,Dedeurwaerdere Stefanie,Kessels Helmut W,Surges Rainer,Rüber Theodor,Gorter Jan A,Mills James D,van Vliet Erwin A,Aronica Eleonora Acta neuropathologica Neuronal dysfunction due to iron accumulation in conjunction with reactive oxygen species (ROS) could represent an important, yet underappreciated, component of the epileptogenic process. However, to date, alterations in iron metabolism in the epileptogenic brain have not been addressed in detail. Iron-related neuropathology and antioxidant metabolic processes were investigated in resected brain tissue from patients with temporal lobe epilepsy and hippocampal sclerosis (TLE-HS), post-mortem brain tissue from patients who died after status epilepticus (SE) as well as brain tissue from the electrically induced SE rat model of TLE. Magnetic susceptibility of the presumed seizure-onset zone from three patients with focal epilepsy was compared during and after seizure activity. Finally, the cellular effects of iron overload were studied in vitro using an acute mouse hippocampal slice preparation and cultured human fetal astrocytes. While iron-accumulating neurons had a pyknotic morphology, astrocytes appeared to acquire iron-sequestrating capacity as indicated by prominent ferritin expression and iron retention in the hippocampus of patients with SE or TLE. Interictal to postictal comparison revealed increased magnetic susceptibility in the seizure-onset zone of epilepsy patients. Post-SE rats had consistently higher hippocampal iron levels during the acute and chronic phase (when spontaneous recurrent seizures are evident). In vitro, in acute slices that were exposed to iron, neurons readily took up iron, which was exacerbated by induced epileptiform activity. Human astrocyte cultures challenged with iron and ROS increased their antioxidant and iron-binding capacity, but simultaneously developed a pro-inflammatory phenotype upon chronic exposure. These data suggest that seizure-mediated, chronic neuronal iron uptake might play a role in neuronal dysfunction/loss in TLE-HS. On the other hand, astrocytes sequester iron, specifically in chronic epilepsy. This function might transform astrocytes into a highly resistant, pro-inflammatory phenotype potentially contributing to pro-epileptogenic inflammatory processes. 10.1007/s00401-021-02348-6
NCOA4 is regulated by HIF and mediates mobilization of murine hepatic iron stores after blood loss. Li Xiuqi,Lozovatsky Larisa,Sukumaran Abitha,Gonzalez Luis,Jain Anisha,Liu Dong,Ayala-Lopez Nadia,Finberg Karin E Blood The mechanisms by which phlebotomy promotes the mobilization of hepatic iron stores are not well understood. NCOA4 (nuclear receptor coactivator 4) is a widely expressed intracellular protein previously shown to mediate the autophagic degradation of ferritin. Here, we investigate a local requirement for NCOA4 in the regulation of hepatic iron stores and examine mechanisms of NCOA4 regulation. Hepatocyte-targeted Ncoa4 knockdown in nonphlebotomized mice had only modest effects on hepatic ferritin subunit levels and nonheme iron concentration. After phlebotomy, mice with hepatocyte-targeted Ncoa4 knockdown exhibited anemia and hypoferremia similar to control mice with intact Ncoa4 regulation but showed a markedly impaired ability to lower hepatic ferritin subunit levels and hepatic nonheme iron concentration. This impaired hepatic response was observed even when dietary iron was limited. In both human and murine hepatoma cell lines, treatment with chemicals that stabilize hypoxia inducible factor (HIF), including desferrioxamine, cobalt chloride, and dimethyloxalylglycine, raised NCOA4 messenger RNA. This NCOA4 messenger RNA induction occurred within 3 hours, preceded a rise in NCOA4 protein, and was attenuated in the setting of dual HIF-1α and HIF-2α knockdown. In summary, we show for the first time that NCOA4 plays a local role in facilitating iron mobilization from the liver after blood loss and that HIF regulates NCOA4 expression in cells of hepatic origin. Because the prolyl hydroxylases that regulate HIF stability are oxygen- and iron-dependent enzymes, our findings suggest a novel mechanism by which hypoxia and iron deficiency may modulate NCOA4 expression to impact iron homeostasis. 10.1182/blood.2020006321
Effect of ultra-short-term treatment of patients with iron deficiency or anaemia undergoing cardiac surgery: a prospective randomised trial. Spahn Donat R,Schoenrath Felix,Spahn Gabriela H,Seifert Burkhardt,Stein Philipp,Theusinger Oliver M,Kaserer Alexander,Hegemann Inga,Hofmann Axel,Maisano Francesco,Falk Volkmar Lancet (London, England) BACKGROUND:Anaemia and iron deficiency are frequent in patients scheduled for cardiac surgery. This study assessed whether immediate preoperative treatment could result in reduced perioperative red blood cell (RBC) transfusions and improved outcome. METHODS:In this single-centre, randomised, double-blind, parallel-group controlled study, patients undergoing elective cardiac surgery with anaemia (n=253; haemoglobin concentration (Hb) <120 g/L in women and Hb <130 g/L in men) or isolated iron deficiency (n=252; ferritin <100 mcg/L, no anaemia) were enrolled. Participants were randomly assigned (1:1) with the use of a computer-generated range minimisation (allocation probability 0·8) to receive either placebo or combination treatment consisting of a slow infusion of 20 mg/kg ferric carboxymaltose, 40 000 U subcutaneous erythropoietin alpha, 1 mg subcutaneous vitamin B12, and 5 mg oral folic acid or placebo on the day before surgery. Primary outcome was the number of RBC transfusions during the first 7 days. This trial is registered with ClinicalTrials.gov, number NCT02031289. FINDINGS:Between Jan 9, 2014, and July 19, 2017, 1006 patients were enrolled; 505 with anaemia or isolated iron deficiency and 501 in the registry. The combination treatment significantly reduced RBC transfusions from a median of one unit in the placebo group (IQR 0-3) to zero units in the treatment group (0-2, during the first 7 days (odds ratio 0·70 [95% CI 0·50-0·98] for each threshold of number of RBC transfusions, p=0·036) and until postoperative day 90 (p=0·018). Despite fewer RBC units transfused, patients in the treatment group had a higher haemoglobin concentration, higher reticulocyte count, and a higher reticulocyte haemoglobin content during the first 7 days (p≤0·001). Combined allogeneic transfusions were less in the treatment group (0 [IQR 0-2]) versus the placebo group (1 [0-3]) during the first 7 days (p=0·038) and until postoperative day 90 (p=0·019). 73 (30%) serious adverse events were reported in the treatment group group versus 79 (33%) in the placebo group. INTERPRETATION:An ultra-short-term combination treatment with intravenous iron, subcutaneous erythropoietin alpha, vitamin B12, and oral folic acid reduced RBC and total allogeneic blood product transfusions in patients with preoperative anaemia or isolated iron deficiency undergoing elective cardiac surgery. FUNDING:Vifor Pharma and Swiss Foundation for Anaesthesia Research. 10.1016/S0140-6736(18)32555-8
A SARS-CoV-2 ferritin nanoparticle vaccine elicits protective immune responses in nonhuman primates. Science translational medicine The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants stresses the continued need for next-generation vaccines that confer broad protection against coronavirus disease 2019 (COVID-19). We developed and evaluated an adjuvanted SARS-CoV-2 spike ferritin nanoparticle (SpFN) vaccine in nonhuman primates. High-dose (50 μg) SpFN vaccine, given twice 28 days apart, induced a Th1-biased CD4 T cell helper response and elicited neutralizing antibodies against SARS-CoV-2 wild-type and variants of concern, as well as against SARS-CoV-1. These potent humoral and cell-mediated immune responses translated into rapid elimination of replicating virus in the upper and lower airways and lung parenchyma of nonhuman primates following high-dose SARS-CoV-2 respiratory challenge. The immune response elicited by SpFN vaccination and resulting efficacy in nonhuman primates supports the utility of SpFN as a vaccine candidate for SARS-causing betacoronaviruses. 10.1126/scitranslmed.abi5735
CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles. Yanatori Izumi,Richardson Des R,Dhekne Herschel S,Toyokuni Shinya,Kishi Fumio Blood Extracellular vesicles (EVs) transfer functional molecules between cells. CD63 is a widely recognized EV marker that contributes to EV secretion from cells. However, the regulation of its expression remains largely unknown. Ferritin is a cellular iron storage protein that can also be secreted by the exosome pathway, and serum ferritin levels classically reflect body iron stores. Iron metabolism-associated proteins such as ferritin are intricately regulated by cellular iron levels via the iron responsive element-iron regulatory protein (IRE-IRP) system. Herein, we present a novel mechanism demonstrating that the expression of the EV-associated protein CD63 is under the regulation of the IRE-IRP system. We discovered a canonical IRE in the 5' untranslated region of CD63 messenger RNA that is responsible for regulating its expression in response to increased iron. Cellular iron loading caused a marked increase in CD63 expression and the secretion of CD63+ EVs from cells, which were shown to contain ferritin-H and ferritin-L. Our results demonstrate that under iron loading, intracellular ferritin is transferred via nuclear receptor coactivator 4 (NCOA4) to CD63+ EVs that are then secreted. Such iron-regulated secretion of the major iron storage protein ferritin via CD63+ EVs, is significant for understanding the local cell-to-cell exchange of ferritin and iron. 10.1182/blood.2021010995
Apolipoprotein E potently inhibits ferroptosis by blocking ferritinophagy. Molecular psychiatry Allelic variation to the APOE gene confers the greatest genetic risk for sporadic Alzheimer's disease (AD). Independent of genotype, low abundance of apolipoprotein E (apoE), is characteristic of AD CSF, and predicts cognitive decline. The mechanisms underlying the genotype and apoE level risks are uncertain. Recent fluid and imaging biomarker studies have revealed an unexpected link between apoE and brain iron, which also forecasts disease progression, possibly through ferroptosis, an iron-dependent regulated cell death pathway. Here, we report that apoE is a potent inhibitor of ferroptosis (EC ≈ 10 nM; N27 neurons). We demonstrate that apoE signals to activate the PI3K/AKT pathway that then inhibits the autophagic degradation of ferritin (ferritinophagy), thus averting iron-dependent lipid peroxidation. Using postmortem inferior temporal brain cortex tissue from deceased subjects from the Rush Memory and Aging Project (MAP) (N = 608), we found that the association of iron with pathologically confirmed clinical Alzheimer's disease was stronger among those with the adverse APOE-ε4 allele. While protection against ferroptosis did not differ between apoE isoforms in vitro, other features of ε4 carriers, such as low abundance of apoE protein and higher levels of polyunsaturated fatty acids (which fuel ferroptosis) could mediate the ε4 allele's heighted risk of AD. These data support ferroptosis as a putative pathway to explain the major genetic risk associated with late onset AD. 10.1038/s41380-022-01568-w
Coordinated Transcriptional and Catabolic Programs Support Iron-Dependent Adaptation to RAS-MAPK Pathway Inhibition in Pancreatic Cancer. Cancer discovery The mechanisms underlying metabolic adaptation of pancreatic ductal adenocarcinoma (PDA) cells to pharmacologic inhibition of RAS-MAPK signaling are largely unknown. Using transcriptome and chromatin immunoprecipitation profiling of PDA cells treated with the MEK inhibitor (MEKi) trametinib, we identify transcriptional antagonism between c-MYC and the master transcription factors for lysosome gene expression, the MiT/TFE proteins. Under baseline conditions, c-MYC and MiT/TFE factors compete for binding to lysosome gene promoters to fine-tune gene expression. Treatment of PDA cells or patient organoids with MEKi leads to c-MYC downregulation and increased MiT/TFE-dependent lysosome biogenesis. Quantitative proteomics of immunopurified lysosomes uncovered reliance on ferritinophagy, the selective degradation of the iron storage complex ferritin, in MEKi-treated cells. Ferritinophagy promotes mitochondrial iron-sulfur cluster protein synthesis and enhanced mitochondrial respiration. Accordingly, suppressing iron utilization sensitizes PDA cells to MEKi, highlighting a critical and targetable reliance on lysosome-dependent iron supply during adaptation to KRAS-MAPK inhibition. SIGNIFICANCE:Reduced c-MYC levels following MAPK pathway suppression facilitate the upregulation of autophagy and lysosome biogenesis. Increased autophagy-lysosome activity is required for increased ferritinophagy-mediated iron supply, which supports mitochondrial respiration under therapy stress. Disruption of ferritinophagy synergizes with KRAS-MAPK inhibition and blocks PDA growth, thus highlighting a key targetable metabolic dependency. See related commentary by Jain and Amaravadi, p. 2023. See related article by Santana-Codina et al., p. 2180. This article is highlighted in the In This Issue feature, p. 2007. 10.1158/2159-8290.CD-22-0044
Effects of Iron Isomaltoside vs Ferric Carboxymaltose on Hypophosphatemia in Iron-Deficiency Anemia: Two Randomized Clinical Trials. JAMA Importance:Intravenous iron enables rapid correction of iron-deficiency anemia, but certain formulations induce fibroblast growth factor 23-mediated hypophosphatemia. Objective:To compare risks of hypophosphatemia and effects on biomarkers of mineral and bone homeostasis of intravenous iron isomaltoside (now known as ferric derisomaltose) vs ferric carboxymaltose. Design, Setting, and Participants:Between October 2017 and June 2018, 245 patients aged 18 years and older with iron-deficiency anemia (hemoglobin level ≤11 g/dL; serum ferritin level ≤100 ng/mL) and intolerance or unresponsiveness to 1 month or more of oral iron were recruited from 30 outpatient clinic sites in the United States into 2 identically designed, open-label, randomized clinical trials. Patients with reduced kidney function were excluded. Serum phosphate and 12 additional biomarkers of mineral and bone homeostasis were measured on days 0, 1, 7, 8, 14, 21, and 35. The date of final follow-up was June 19, 2018, for trial A and May 29, 2018, for trial B. Interventions:Intravenous administration of iron isomaltoside, 1000 mg, on day 0 or ferric carboxymaltose, 750 mg, infused on days 0 and 7. Main Outcomes and Measures:The primary end point was the incidence of hypophosphatemia (serum phosphate level <2.0 mg/dL) between baseline and day 35. Results:In trial A, 123 patients were randomized (mean [SD] age, 45.1 [11.0] years; 95.9% women), including 62 to iron isomaltoside and 61 to ferric carboxymaltose; 95.1% completed the trial. In trial B, 122 patients were randomized (mean [SD] age, 42.6 [12.2] years; 94.1% women), including 61 to iron isomaltoside and 61 to ferric carboxymaltose; 93.4% completed the trial. The incidence of hypophosphatemia was significantly lower following iron isomaltoside vs ferric carboxymaltose (trial A: 7.9% vs 75.0% [adjusted rate difference, -67.0% {95% CI, -77.4% to -51.5%}], P < .001; trial B: 8.1% vs 73.7% [adjusted rate difference, -65.8% {95% CI, -76.6% to -49.8%}], P < .001). Beyond hypophosphatemia and increased parathyroid hormone, the most common adverse drug reactions (No./total No.) were nausea (iron isomaltoside: 1/125; ferric carboxymaltose: 8/117) and headache (iron isomaltoside: 4/125; ferric carboxymaltose: 5/117). Conclusions and Relevance:In 2 randomized trials of patients with iron-deficiency anemia who were intolerant of or unresponsive to oral iron, iron isomaltoside (now called ferric derisomaltose), compared with ferric carboxymaltose, resulted in lower incidence of hypophosphatemia over 35 days. However, further research is needed to determine the clinical importance of this difference. Trial Registration:ClinicalTrials.gov Identifiers: NCT03238911 and NCT03237065. 10.1001/jama.2019.22450
Association Between Hemoglobin Levels and Efficacy of Intravenous Ferric Carboxymaltose in Patients With Acute Heart Failure and Iron Deficiency: An AFFIRM-AHF Subgroup Analysis. Circulation BACKGROUND:Iron deficiency, with or without anemia, is an adverse prognostic factor in heart failure (HF). In AFFIRM-AHF (a randomized, double-blind placebo-controlled trial comparing the effect of intravenous ferric carboxymaltose on hospitalizations and mortality in iron-deficient subjects admitted for acute heart failure), intravenous ferric carboxymaltose (FCM), although having no significant effect on the primary end point, reduced the risk of HF hospitalization (hHF) and improved quality of life versus placebo in iron-deficient patients stabilized after an acute HF (AHF) episode. These prespecified AFFIRM-AHF subanalyses explored the association between hemoglobin levels and FCM treatment effects. METHODS:AFFIRM-AHF was a multicenter, double-blind, randomized, placebo-controlled trial of FCM in hospitalized AHF patients with iron deficiency. Patients were stratified by baseline hemoglobin level (<12 versus ≥12 g/dL). In each subgroup, the primary composite (total hHF and cardiovascular death) and secondary (total hHF; total cardiovascular hospitalizations and cardiovascular death; time to cardiovascular death, and time to first/days lost due to hHF or cardiovascular death) outcomes were assessed with FCM versus placebo at week 52. Sensitivity analyses using the World Health Organization anemia definition (hemoglobin level <12 g/dL [women] or <13 g/dL [men]) were performed, among others. RESULTS:Of 1108 AFFIRM-AHF patients, 1107 were included in these subanalyses: 464 (FCM group, 228; placebo group, 236) had a hemoglobin level <12 g/dL, and 643 (FCM, 329; placebo, 314) had a hemoglobin level ≥12 g/dL. Patients with a hemoglobin level <12 g/dL were older (mean, 73.7 versus 69.1 years), with more frequent previous HF (75.0% versus 68.7%), serum ferritin <100 μg/L (75.4% versus 68.1%), and transferrin saturation <20% (87.9% versus 81.4%). For the primary outcome, annualized event rates per 100 patient-years with FCM versus placebo were 71.1 and 73.6 (rate ratio, 0.97 [95% CI, 0.66-1.41]), respectively, and 48.5 versus 72.9 (RR, 0.67 [95% CI, 0.48-0.93]) in the hemoglobin levels <12 and ≥12 g/dL subgroups, respectively. No significant interactions between hemoglobin subgroup and treatment effect were observed for primary (=0.15) or secondary outcomes. Changes from baseline in hemoglobin, serum ferritin and transferrin saturation were significantly greater with FCM versus placebo in both subgroups between weeks 6 and 52. Findings were similar using the World Health Organization definition for anemia. CONCLUSIONS:The effects of intravenous FCM on outcomes in iron-deficient patients stabilized after an AHF episode, including improvements in iron parameters over time, did not differ between patients with hemoglobin levels <12 and ≥12 g/dL. REGISTRATION:URL: https://www. CLINICALTRIALS:gov; Unique identifier: NCT02937454. 10.1161/CIRCULATIONAHA.122.060757
Elevated Liver Enzymes, Ferritin, C-reactive Protein, D-dimer, and Age Are Predictive Markers of Outcomes Among African American and Hispanic Patients With Coronavirus Disease 2019. Ashktorab Hassan,Pizuorno Antonio,Aduli Farshad,Laiyemo Adeyinka O,Oskrochi Gholamreza,Brim Hassan Gastroenterology 10.1053/j.gastro.2021.03.043
Shielding Ferritin with a Biomineralized Shell Enables Efficient Modulation of Tumor Microenvironment and Targeted Delivery of Diverse Therapeutic Agents. Wang Changlong,Wang Xiaojun,Zhang Wei,Ma Ding,Li Feng,Jia Rongrong,Shi Min,Wang Yugang,Ma Guanghui,Wei Wei Advanced materials (Deerfield Beach, Fla.) Ferritin (Fn) is considered a promising carrier for targeted delivery to tumors, but the successful application in vivo has not been fully achieved yet. Herein, strong evidence is provided that the Fn receptor is expressed in liver tissues, resulting in an intercept effect in regards to tumor delivery. Building on these observations, a biomineralization technology is rationally designed to shield Fn using a calcium phosphate (CaP) shell, which can improve the delivery performance by reducing Fn interception in the liver while re-exposing it in acidic tumors. Moreover, the selective dissolution of the CaP shell not only neutralizes the acidic microenvironment but also induces the intratumoral immunomodulation and calcification. Upon multiple cell line and patient-derived xenografts, it is demonstrated that the elaboration of the highly flexible Fn@CaP chassis by loading a chemotherapeutic drug into the Fn cavity confers potent antitumor effects, and additionally encapsulating a photosensitizer into the outer shell enables a combined chemo-photothermal therapy for complete suppression of advanced tumors. Altogether, these results support Fn@CaP as a new nanoplatform for efficient modulation of the tumor microenvironment and targeted delivery of diverse therapeutic agents. 10.1002/adma.202107150
Mycobacterium tuberculosis hijacks host TRIM21- and NCOA4-dependent ferritinophagy to enhance intracellular growth. The Journal of clinical investigation Ferritin, a key regulator of iron homeostasis in macrophages, has been reported to confer host defenses against Mycobacterium tuberculosis (Mtb) infection. Nuclear receptor coactivator 4 (NCOA4) was recently identified as a cargo receptor in ferritin degradation. Here, we show that Mtb infection enhanced NCOA4-mediated ferritin degradation in macrophages, which in turn increased the bioavailability of iron to intracellular Mtb and therefore promoted bacterial growth. Of clinical relevance, the upregulation of FTH1 in macrophages was associated with tuberculosis (TB) disease progression in humans. Mechanistically, Mtb infection enhanced NCOA4-mediated ferritin degradation through p38/AKT1- and TRIM21-mediated proteasomal degradation of HERC2, an E3 ligase of NCOA4. Finally, we confirmed that NCOA4 deficiency in myeloid cells expedites the clearance of Mtb infection in a murine model. Together, our findings revealed a strategy by which Mtb hijacks host ferritin metabolism for its own intracellular survival. Therefore, this represents a potential target for host-directed therapy against tuberculosis. 10.1172/JCI159941
Cargo loading within ferritin nanocages in preparation for tumor-targeted delivery. Nature protocols Ferritins are spherical iron storage proteins within cells, composed of 24 subunits of two types, heavy-chain ferritin (HFn) and light-chain ferritin. Ferritins auto-assemble naturally into hollow nanocages with an outer diameter of 12 nm and an interior cavity 8 nm in diameter. Since the intrinsic tumor-targeting property of human HFn was first reported in 2012, HFn has been extensively explored for tumor-targeted delivery of anticancer drugs and diagnostic molecules, including radioisotopes and fluorophores, as well as inorganic nanoparticles (NPs) and chemotherapeutic drugs. This protocol provides four detailed procedures describing how to load four types of cargoes within HFn nanocages that are capable of accurately controlling cargo loading: synthesis of inorganic metal nanoparticles within the cavity of a wild-type human HFn nanocage (Procedure 1, requires ~5 h); loading of doxorubicin into the cavity of a wild-type human HFn nanocage (Procedure 2, requires ~3 d); loading Gd into the cavity of a genetically engineered human HFn nanocage (Procedure 3, requires ~20 h); and loading Cu radioisotope into the cavity of a genetically engineered human HFn nanocage (Procedure 4, requires ~3 h). Subsequent use of these HFn-based formulations is advantageous as they have intrinsic tumor-targeting capability and lack immunogenicity. Human HFn generated as described in this protocol can therefore be used to deliver therapeutic drugs and diagnostic signals as multifunctional nanomedicines. 10.1038/s41596-021-00602-5
Clinical and immunological features of severe and moderate coronavirus disease 2019. Chen Guang,Wu Di,Guo Wei,Cao Yong,Huang Da,Wang Hongwu,Wang Tao,Zhang Xiaoyun,Chen Huilong,Yu Haijing,Zhang Xiaoping,Zhang Minxia,Wu Shiji,Song Jianxin,Chen Tao,Han Meifang,Li Shusheng,Luo Xiaoping,Zhao Jianping,Ning Qin The Journal of clinical investigation BACKGROUNDSince December 2019, an outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, and is now becoming a global threat. We aimed to delineate and compare the immunological features of severe and moderate COVID-19.METHODSIn this retrospective study, the clinical and immunological characteristics of 21 patients (17 male and 4 female) with COVID-19 were analyzed. These patients were classified as severe (11 cases) and moderate (10 cases) according to the guidelines released by the National Health Commission of China.RESULTSThe median age of severe and moderate cases was 61.0 and 52.0 years, respectively. Common clinical manifestations included fever, cough, and fatigue. Compared with moderate cases, severe cases more frequently had dyspnea, lymphopenia, and hypoalbuminemia, with higher levels of alanine aminotransferase, lactate dehydrogenase, C-reactive protein, ferritin, and D-dimer as well as markedly higher levels of IL-2R, IL-6, IL-10, and TNF-α. Absolute numbers of T lymphocytes, CD4+ T cells, and CD8+ T cells decreased in nearly all the patients, and were markedly lower in severe cases (294.0, 177.5, and 89.0 × 106/L, respectively) than moderate cases (640.5, 381.5, and 254.0 × 106/L, respectively). The expression of IFN-γ by CD4+ T cells tended to be lower in severe cases (14.1%) than in moderate cases (22.8%).CONCLUSIONThe SARS-CoV-2 infection may affect primarily T lymphocytes, particularly CD4+ and CD8+ T cells, resulting in a decrease in numbers as well as IFN-γ production by CD4+ T cells. These potential immunological markers may be of importance because of their correlation with disease severity in COVID-19.TRIAL REGISTRATIONThis is a retrospective observational study without a trial registration number.FUNDINGThis work is funded by grants from Tongji Hospital for the Pilot Scheme Project, and partly supported by the Chinese National Thirteenth Five Years Project in Science and Technology for Infectious Disease (2017ZX10202201). 10.1172/JCI137244
Analysis of inflammatory parameters and disease severity for 88 hospitalized COVID-19 patients in Wuhan, China. International journal of medical sciences The outbreak of coronavirus disease 2019 (COVID-19) is quickly turning into a pandemic. We aimed to further clarify the clinical characteristics and the relationship between these features and disease severity. In this retrospective single-center study, demographic, clinical and laboratory data were collected and analyzed among moderate, severe and critically ill group patients. 88 hospitalization patients confirmed COVID-19 were enrolled in this study. The average age of the patients was 57.11 years (SD, ±15.39). Of these 88 patients, the median body mass index (BMI) was 24.03 (IQR, 21.64-26.61; range 15.05-32.39), the median duration from disease onset to hospital admission were 11 days (IQR, 6.50-14.50). 46.59% patients had one or more comorbidities, with hypertension being the most common (26.14%), followed by diabetes mellitus (12.50%) and coronary atherosclerotic heart disease (CAD) (7.95%). Common symptoms at onset of disease were fever (71.59%), cough (59.09%), dyspnea (38.64%) and fatigue (29.55%). 88 patients were divided into moderate (47 [53.41%]), severe (32 [36.36%]) and critically ill (9 [10.23%]) groups. Compared with severe and moderate patients, lymphocytopenia occurred in 85.71% critically ill patients, and serum IL-2R, IL-6, IL-8, TNF-α, LDH, and cTnI were also increased in 71.42%, 83.33%, 57.14%, 71.43%, 100% and 42.86% in critically ill patients. Through our analysis, the age, comorbidities, lymphocyte count, eosinophil count, ferritin, CRP, LDH, PT and inflammatory cytokines were statistically significant along with the disease severity. We found some clinical characteristic and inflammatory cytokines could reveal the severity of COVID-19 during the outbreak phage. Our research could assist the clinicians recognize severe and critically ill patients timely and focus on the expectant treatment for each patient. 10.7150/ijms.47935
Inflammatory biomarkers and severity of COVID-19: Cross sectional study among Egyptian patients. The Egyptian journal of immunology The newly emerging coronavirus disease 2019 (COVID-19) is characterized by multisystem inflammatory syndrome. The development of SARS-CoV-2 complications usually starts within few days following infection, and the severity of the disease determines its outcome. Vitamin D insufficiency is associated with risk of lung infections, also cell-based studies reported the ability of vitamin D to control enveloped virus growth. We aimed to investigate the relationship between the most eminent inflammatory biomarkers and the level of vitamin D aiming to provide a tool for early diagnosis and prediction of disease progression. The current study was approved by Research Ethics Committee (REC), Kasr Al-Ainy. After confirmation of being COVID-19 by PCR, the admitted patients were categorized as mild-moderate, and severe-critically ill based on clinical and radiologic data. The total levels of serum 25(OH)D, as well as other pro-inflammatory biomarkers were measured and were analyzed by receiver operating characteristic curve (ROC) analysis for detection of their association with COVID-19 disease severity and to determine their sensitivity and specificity at optimum cutoff points. The area under the curve (AUC) ROC for predicting COVID-19 disease severity was the highest (of 0.97) for vitamin D, inflammatory cytokines, liver enzymes, ferritin, and D-Dimer. In addition, high serum levels of creatinine, and elevated liver enzymes associated with severe-critical COVID-19. The low 25(OH)D was associated with the disease severity.
Clinical significance of serum ferritin in patients with systemic sclerosis. Journal of clinical laboratory analysis OBJECTIVE:The purpose of this study was to explore the clinical significance of serum ferritin (SF) in patients with systemic sclerosis (SSc). METHODS:The levels of SF were measured in 115 patients with SSc and 117 healthy controls (HCs). Clinical characteristics and laboratory indexes between the high ferritin SSc group and the normal ferritin SSc group were analyzed. RESULTS:The level of SF in SSc patients was significantly higher than that in HCs (319.78 [179, 554.33] ng/ml vs. 99 [49.03, 164.29] ng/ml, p < 0.01). Compared with the normal ferritin SSc group, the high ferritin SSc group was more likely to develop skin diffuse cutaneous SSc, fingertip arthralgia, and cardiac involvement. In addition, the levels of glutamine transaminase (GGT), alanine aminotransferase (ALT), creatine kinase (CK), creatine kinase isoenzyme-MB (CK-MB), lactate dehydrogenase (LD), immunoglobulin G (IgG), immunoglobulin A (IgA), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and the positive rate of anti-Scl70 antibody in the high ferritin SSc group were significantly higher (each p < 0.05). SF was positively correlated with GGT, ALT, CK, CK-MB, LD, IgA, CRP, and ESR (each p < 0.05). Multiple linear regression analysis showed that cardiac involvement, ALT, and ESR were independent influencing factors of SF in SSc. CONCLUSION:Our study shows that the level of SF in patients with SSc is increased, and the elevated SF is related to abnormal liver function, myocardial involvement, inflammatory status, and production of autoantibodies in SSc. Cardiac involvement, ALT, and ESR are independent factors affecting SF in SSc. 10.1002/jcla.24597
[Relevant immunologic markers in COVID-19]. Admou Brahim The Pan African medical journal In its severe form, corona virus disease-19 (COVID-19) is characterized by various immunological abnormalities, dominated by massive pro-inflammatory cytokine and chemokine release, such as IL-6, TNF-α, IL-1b, IFN-y and monocyte chemoattractant protein-1 (MCP-1), associated with T CD3, T CD4 and T CD8 lymphopenia. These two abnormalities are significantly associated with COVID-19 acute severe respiratory syndrome. Conversely, these markers decrease during the favorable course of the disease. Coupled with other biological parameters such as leukopenia, increased level of CRP (C Reactive Protein), ferritin and D-dimers, high levels of IL-6 with CD4 and CD8 T cell lymphopenia may be considered as criteria of disease severity, justifying a rapid admission to the intensive care unit, and are also useful for patient monitoring. 10.11604/pamj.2021.39.40.23481
Prognostic value of interleukin-18 and its association with other inflammatory markers and disease severity in COVID-19. Cytokine BACKGROUND:The effectual immune response is crucial to defeat viral infections. However, exuberant immune response with features of macrophage activation syndrome (MAS) lead detrimental consequences in COVID-19 patients. Interleukin (IL)-18 is one of the leading cytokines in MAS which has not been studied in COVID-19. OBJECTIVE:To investigate the association of IL-18 with the other inflammatory markers and disease severity in COVID-19 for predicting disease prognosis. METHODS:Patients with COVID-19 who had confirmed diagnosis with SARS-CoV-2 nucleic acid RT-PCR were enrolled into the study. Data on demographic and clinical characteristics, and laboratory values of CRP, ferritin, d-dimer and procalcitonin were measured on admission. Patients were followed up prospectively with a standardized approach until hospital discharge or death. Individuals were classified as asymptomatic, mild and severe pneumonia according to their clinical, laboratory and radiological characteristics. Worse outcome was defined as requirement of intensive care unit (ICU) admission or death. Blood samples were collected at enrollment and serum levels of IL-6 and IL-18 were determined by ELISA. Association between IL-18 and other inflammatory markers and prognosis were analyzed. RESULTS:There were 58 COVID-19 patients (50% male) with a median age of 43 (min 22-max 81) years. Twenty age and sex matched healthy subjects were served as control group. The study population was divided into three groups according to disease severity: asymptomatic (n = 20), mild pneumonia group (n = 27) and a severe group (n = 11). During follow up nine (15.5%) patients required ICU admission and three of them were died eventually. Serum IL-18 were correlated with other inflammatory markers and biochemical markers of organ injury; creatinine, liver enzymes and troponin. Serum IL-18 levels were remarkably higher in COVID-19 patients compared to healthy subjects with being highest in severe pneumonia group (p < 0.001). IL-18 serum concentrations were almost four-fold higher in patients with worse outcome compared to good outcome (p < 0.001). Serum IL-18 above the cut off value of 576 pg/mL on admission was associated with 11.7 fold increased risk of ICU admission. CONCLUSIONS:The serum concentrations of IL-18 correlate with other inflammatory markers and reflect disease severity. Results of the present study shed light on role of IL-18 on COVID-19 pathogenesis and might provide an evidence for the clinical trials on IL-18 antagonists for the treatment of severe COVID-19 patients. 10.1016/j.cyto.2020.155302
Inflammatory markers and control of type 2 diabetes mellitus. Elimam Hanan,Abdulla Azza M,Taha Inas Mohamed Diabetes & metabolic syndrome BACKGROUND:Subclinical inflammation and presence of almost all indicators of systemic inflammation are found in type 2 diabetic patients. Such a systemic and subclinical inflammatory process can be characterized by elevated circulating levels of inflammatory markers. AIM:To study the state of subclinical inflammation in patients with type 2 diabetes mellitus and establish a correlation between glycemic control and inflammatory markers. METHODS:This research included 90 subjects divided into 2 groups; Group A: 70 patients with type 2 diabetes and Group B: 20 Age and sex matched people as the control group. All patients were clinically examined, had laboratory investigations including; fasting and 2 h postprandial blood sugar, HbA1c, serum ferritin., high sensitivity C-reactive protein hs-CRP, kidney functions tests, liver function tests, complete blood count and erythrocyte sedimentation rate and antinuclear antibody. RESULTS:The estimated levels of ESR, FBS, serum ferritin, hs-CRP and HbA1c in T2DM were 10.69 ± 3.05, 186.01 ± 92.21, 6005.2 ± 2639.83, 155.75 ± 73.95, 7.5 ± 3.23, respectively. In a similar way, in control subject, the estimated levels for respective parameters were 12.4 ± 3.41, 83.25 ± 6.25, 45.088 ± 39.35, 19.97 ± 18.51, 4.555 ± 0.58, respectively. Mean values of all parameters, except ESR, were found to be significantly augmented in T2DM subjects when compared to control group. There is significant positive correlation between HbA1c and hs-CRP (r=0.761, p < 0.001). Moreover, serum ferritin has shown significant positive correlation with HbA1c (r = 0.853, p < 0.001). CONCLUSION:Strong correlation between inflammation and glycemic control in patient with type 2 diabetes mellitus suggests that inflammation plays an important role in the pathogenesis of diabetes. 10.1016/j.dsx.2018.11.061
Soluble transferrin receptor and soluble transferrin receptor/log ferritin index in diagnosis of iron deficiency anemia in pediatric inflammatory bowel disease. Krawiec Paulina,Pac-Kożuchowska Elżbieta Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver BACKGROUND:There is no single reliable marker of iron homeostasis in inflammatory bowel disease. AIMS:To determine diagnostic usefulness of soluble transferrin receptor and soluble transferrin receptor/log ferritin index in iron deficiency anemia in children with inflammatory bowel disease. METHODS:We assessed soluble transferrin receptor in serum and calculated soluble transferrin receptor/log ferritin index in 75 children with inflammatory bowel disease. Diagnostic ability to identify iron deficiency anemia was examined by receiver operating characteristic analysis. RESULTS:Study group comprised 27 cases of iron deficiency anemia, 6 anemia of chronic disease with iron deficiency, 5 anemia of chronic disease. Soluble transferrin receptor was significantly increased in children with iron deficiency anemia (median: 1.63 μg/ml) compared to non-anemic children (median: 1.02 μg/ml). Soluble transferrin receptor/log ferritin index was significantly higher in iron deficiency anemia (median: 1.76) than in anemia of chronic disease (median: 0.55), anemia of chronic disease with iron deficiency (median: 0.68) or patients without anemia (median: 0.72). Soluble transferrin receptor and its index were not correlated with disease activity or inflammatory markers. Diagnostic power for soluble transferrin receptor/log ferritin index (0.864) was superior to soluble transferrin receptor (0.768) in iron deficiency anemia recognition. CONCLUSION:Soluble transferrin receptor/log ferritin index has better diagnostic utility than soluble transferrin receptor for iron deficiency anemia detection in pediatric inflammatory bowel disease. 10.1016/j.dld.2018.11.012
Predictors of adverse prognosis in COVID-19: A systematic review and meta-analysis. Figliozzi Stefano,Masci Pier Giorgio,Ahmadi Navid,Tondi Lara,Koutli Evangelia,Aimo Alberto,Stamatelopoulos Kimon,Dimopoulos Meletios-Athanasios,Caforio Alida L P,Georgiopoulos Georgios European journal of clinical investigation BACKGROUND:Identification of reliable outcome predictors in coronavirus disease 2019 (COVID-19) is of paramount importance for improving patient's management. METHODS:A systematic review of literature was conducted until 24 April 2020. From 6843 articles, 49 studies were selected for a pooled assessment; cumulative statistics for age and sex were retrieved in 587 790 and 602 234 cases. Two endpoints were defined: (a) a composite outcome including death, severe presentation, hospitalization in the intensive care unit (ICU) and/or mechanical ventilation; and (b) in-hospital mortality. We extracted numeric data on patients' characteristics and cases with adverse outcomes and employed inverse variance random-effects models to derive pooled estimates. RESULTS:We identified 18 and 12 factors associated with the composite endpoint and death, respectively. Among those, a history of CVD (odds ratio (OR) = 3.15, 95% confidence intervals (CIs) 2.26-4.41), acute cardiac (OR = 10.58, 5.00-22.40) or kidney (OR = 5.13, 1.78-14.83) injury, increased procalcitonin (OR = 4.8, 2.034-11.31) or D-dimer (OR = 3.7, 1.74-7.89), and thrombocytopenia (OR = 6.23, 1.031-37.67) conveyed the highest odds for the adverse composite endpoint. Advanced age, male sex, cardiovascular comorbidities, acute cardiac or kidney injury, lymphocytopenia and D-dimer conferred an increased risk of in-hospital death. With respect to the treatment of the acute phase, therapy with steroids was associated with the adverse composite endpoint (OR = 3.61, 95% CI 1.934-6.73), but not with mortality. CONCLUSIONS:Advanced age, comorbidities, abnormal inflammatory and organ injury circulating biomarkers captured patients with an adverse clinical outcome. Clinical history and laboratory profile may then help identify patients with a higher risk of in-hospital mortality. 10.1111/eci.13362
Interleukin-6, procalcitonin and neutrophil-to-lymphocyte ratio: Potential immune-inflammatory parameters to identify severe and fatal forms of COVID-19. Cytokine Accumulating evidence supports that the viral-induced hyper-inflammatory immune response plays a central role in COVID-19 pathogenesis. It might be involved in the progression to acute respiratory distress syndrome (ARDS), multi-organ failure leading to death. In this study, we aimed to evaluate the prognostic value of the immune-inflammatory biomarkers in COVID-19, then determine optimal thresholds for assessing severe and fatal forms of this disease.153 patients with confirmed COVID-19 were included in this study, and classified into non-severe and severe groups. Plasmatic levels of interleukin 6 (IL6), C-reactive protein (CRP), soluble-IL2 receptor (IL2Rα), procalcitonin (PCT) and ferritin were measured using chemiluminescence assay. Complete blood count was performed by Convergys 3X® hematology analyzer. Our results demonstrated that the peripheral blood levels of IL6, PCT, CRP, ferritin, IL2Rα, white blood cell count (WBC), neutrophil count (NEU), neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (d-NLR) were significantly higher in severe forms of COVID-19. The ROC curve analysis showed that IL6 was the most accurate inflammatory biomarker. The calculated cutoff of IL6 (42 pg/ml) could correctly classify > 90% of patients regarding their risk of severity (area under ROC curve (AUROC) = 0.972) and the threshold value of 83 pg/ml was highly predictive of the progression to death (AUROC = 0.94, OR = 184) after a median of 3 days. Besides, IL-6 was positively correlated with other inflammatory markers and the kinetic analysis highlighted its value for monitoring COVID-19 patients. PCT and NLR had also a high prognostic relevance to assess severe forms of COVID-19 with corresponding AUROC of 0.856, 0.831 respectively. Furthermore the cut-off values of PCT (0.16 ng/ml) and NLR (7.4) allowed to predict mortality with high accuracy (se = 96.3%, sp = 70.5%,OR = 61.2)' (se = 75%, sp = 84%, OR = 14.6).The levels of these parameters were not influenced by corticosteroid treatment, which make them potential prognostic markers when patients are already undergoing steroid therapy. 10.1016/j.cyto.2021.155428
IL-6 and other biomarkers as predictors of severity in COVID-19. Annals of medicine OBJECTIVE:Cytokine release syndrome is suggested to be the most important mechanism triggering acute respiratory distress syndrome and end organ damage in COVID-19. The severity of disease may be measured by different biomarkers. METHODS:We studied markers of inflammation and coagulation as recorded in 29 patients on admission to the hospital in order to identify markers of severe COVID-19 and need of ICU. RESULTS:Patients who were eventually admitted to ICU displayed significantly higher serum levels of interleukin-6 (IL-6), C-reactive protein (CRP), and procalcitonin. No statistical differences were found between the groups in median levels of lymphocytes, D-dimer or ferritin. CONCLUSIONS:IL-6 and CRP were the strongest predictors of severity in hospitalized patients with COVID-19. 10.1080/07853890.2020.1840621
An immune-based biomarker signature is associated with mortality in COVID-19 patients. JCI insight Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN-, type II IFN-, and NF-κB-dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients' first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome. 10.1172/jci.insight.144455
EASL Clinical Practice Guidelines on haemochromatosis. Journal of hepatology Haemochromatosis is characterised by elevated transferrin saturation (TSAT) and progressive iron loading that mainly affects the liver. Early diagnosis and treatment by phlebotomy can prevent cirrhosis, hepatocellular carcinoma, diabetes, arthropathy and other complications. In patients homozygous for p.Cys282Tyr in HFE, provisional iron overload based on serum iron parameters (TSAT >45% and ferritin >200 μg/L in females and TSAT >50% and ferritin >300 μg/L in males and postmenopausal women) is sufficient to diagnose haemochromatosis. In patients with high TSAT and elevated ferritin but other HFE genotypes, diagnosis requires the presence of hepatic iron overload on MRI or liver biopsy. The stage of liver fibrosis and other end-organ damage should be carefully assessed at diagnosis because they determine disease management. Patients with advanced fibrosis should be included in a screening programme for hepatocellular carcinoma. Treatment targets for phlebotomy are ferritin <50 μg/L during the induction phase and <100 μg/L during the maintenance phase. 10.1016/j.jhep.2022.03.033
Ferritin self-assembly, structure, function, and biotechnological applications. International journal of biological macromolecules Ferritin is a vital protein complex responsible for storing iron in almost all living organisms. It plays a crucial role in various metabolic pathways, inflammation processes, stress response, and pathogenesis of cancer and neurodegenerative diseases. In this review we discuss the role of ferritin in diseases, cellular iron regulation, its structural features, and its role in biotechnology. We also show that molecular mechanisms of ferritin self-assembly are key for a number of biotechnological and pharmaceutical applications. The assembly pathways strongly depend on the interface context of ferritin monomers and the stability of its different intermediate oligomers. To date, several schemes of self-assembly kinetics have been proposed. Here, we compare different self-assembly mechanisms and discuss the possibility of self-assembly control by switching between deadlock intermediate states. 10.1016/j.ijbiomac.2022.10.126
Iron-induced NCOA4 condensation regulates ferritin fate and iron homeostasis. EMBO reports Iron is not only essential but also a toxic trace element. Under iron repletion, ferritin maintains cellular iron homeostasis by storing iron to avoid iron toxicity. Under iron depletion, the ferritin-specific autophagy adaptor NCOA4 delivers ferritin to lysosomes via macroautophagy to enable cells to use stored iron. Here, we show that NCOA4 also plays crucial roles in the regulation of ferritin fate under iron repletion. NCOA4 forms insoluble condensates via multivalent interactions generated by the binding of iron to its intrinsically disordered region. This sequesters NCOA4 away from ferritin and allows ferritin accumulation in the early phase of iron repletion. Under prolonged iron repletion, NCOA4 condensates can deliver ferritin to lysosomes via a TAX1BP1-dependent non-canonical autophagy pathway, thereby preventing relative iron deficiency due to excessive iron storage and reduced iron uptake. Together, these observations suggest that the NCOA4-ferritin axis modulates intracellular iron homeostasis in accordance with cellular iron availability. 10.15252/embr.202154278
Ferritin in serum and urine: A pilot study. Bahr Timothy M,Christensen Robert D,Ward Diane M,Meng Fanjing,Jackson Laurie K,Doyle Kelly,Christensen Daniel R,Harvey Anne G,Yaish Hassan M Blood cells, molecules & diseases Serum ferritin reflects total body iron stores, thus a low serum ferritin is used as a parameter of iron deficiency. In healthy adults in Japan, urine ferritin levels were about 5% of serum ferritin levels, with a correlation coefficient of 0.79. It is not known whether a low urine ferritin could serve as a non-invasive screen for iron deficiency. If so, this might be useful for neonates and young children, avoiding phlebotomy to screen for iron deficiency. However, for urinary ferritin screening to be feasible, ferritin must be measurable in the urine and correlate with serum ferritin. Testing should also clarify whether the iron content of ferritin in serum and urine are similar. In this pilot feasibility study we measured ferritin in paired serum and urine samples of healthy adult males, healthy term neonates, growing preterm neonates, and children who had very high serum ferritin levels from liver disorders or iron overload. We detected ferritin in every urine sample, and found a correlation with paired serum ferritin (Spearman correlation coefficient 0.78 of log-transformed values). These findings suggest merit in further studying urinary ferritin in select populations, as a potential non-invasive screen to assess iron stores. 10.1016/j.bcmd.2019.02.001
NCOA4 drives ferritin phase separation to facilitate macroferritinophagy and microferritinophagy. The Journal of cell biology A ferritin particle consists of 24 ferritin proteins (FTH1 and FTL) and stores iron ions within it. During iron deficiency, ferritin particles are transported to lysosomes to release iron ions. Two transport pathways have been reported: macroautophagy and ESCRT-dependent endosomal microautophagy. Although the membrane dynamics of these pathways differ, both require NCOA4, which is thought to be an autophagy receptor for ferritin. However, it is unclear whether NCOA4 only acts as an autophagy receptor in ferritin degradation. Here, we found that ferritin particles form liquid-like condensates in a NCOA4-dependent manner. Homodimerization of NCOA4 and interaction between FTH1 and NCOA4 (i.e., multivalent interactions between ferritin particles and NCOA4) were required for the formation of ferritin condensates. Disruption of these interactions impaired ferritin degradation. Time-lapse imaging and three-dimensional correlative light and electron microscopy revealed that these ferritin-NCOA4 condensates were directly engulfed by autophagosomes and endosomes. In contrast, TAX1BP1 was not required for the formation of ferritin-NCOA4 condensates but was required for their incorporation into autophagosomes and endosomes. These results suggest that NCOA4 acts not only as a canonical autophagy receptor but also as a driver to form ferritin condensates to facilitate the degradation of these condensates by macroautophagy (i.e., macroferritinophagy) and endosomal microautophagy (i.e., microferritinophagy). 10.1083/jcb.202203102
Ferritin: A Multifunctional Nanoplatform for Biological Detection, Imaging Diagnosis, and Drug Delivery. Song Ningning,Zhang Jianlin,Zhai Jiao,Hong Juanji,Yuan Chang,Liang Minmin Accounts of chemical research Ferritins are spherical iron storage proteins within cells that are composed of a combination of 24 subunits of two types, heavy-chain ferritin (HFn) and light-chain ferritin (LFn). They autoassemble naturally into a spherical hollow nanocage with an outer diameter of 12 nm and an interior cavity that is 8 nm in diameter. In recent years, with the constantly emerging safety issues and the concerns about unfavorable uniformity and indefinite behavior of traditional nanomedicines, the characteristics of native ferritin nanocages, such as the unique nanocage structure, excellent safety profile, and definite behavior, make ferritin-based formulations uniquely attractive for nanomedicine development. To date, a variety of cargo molecules, including therapeutic drugs (, cisplatin, carboplatin, paclitaxel, curcumin, atropine, quercetin, gefitinib, daunomycin, epirubicin, doxorubicin, etc.), imaging agents (, fluorescence dyes, radioisotopes, and MRI contrast agents), nucleic acids (, siRNA and miRNA), and metal nanoparticles (, FeO, CeO, AuPd, CuS, CoPt, FeCo, Ag, etc.) have been loaded into the interior cavity of ferritin nanocages for a broad range of biomedical applications from biosensing to targeted delivery of cargo molecules in living systems with the aid of modified targeting ligands either genetically or chemically. We reported that human HFn could selectively deliver a large amount of cargo into tumors transferrin receptor 1 (TfR1)-mediated tumor-cell-specific targeting followed by rapid internalization. By the use of the intrinsic tumor-targeting property and unique nanocage structure of human HFn, a broad variety of cargo-loaded HFn formulations have been developed for biological analysis, imaging diagnosis, and medicine development. In view of the intrinsic tumor-targeting property, unique nanocage structure, lack of immunogenicity, and definite behavior, human HFn holds promise to promote therapeutic drugs, diagnostic imaging agents, and targeting moieties into multifunctional nanomedicines.Since the report of the intrinsic tumor-targeting property of human HFn, we have extensively explored human HFn as an ideal nanocarrier for tumor-targeted delivery of anticancer drugs, MRI contrast agents, inorganic nanoparticles, and radioisotopes. In particular, by the use of genetic tools, we also have genetically engineered human HFn nanocages to recognize a broader range of disease biomarkers. In this Account, we systematically review human ferritins from characterizing their tumor-binding property and understanding their mechanism and kinetics for cargo loading to exploring their biomedical applications. We finally discuss the prospect of ferritin-based formulations to become next-generation nanomedicines. We expect that ferritin formulations with unique physicochemical characteristics and intrinsic tumor-targeting property will attract broad interest in fundamental drug research and offer new opportunities for nanomedicine development. 10.1021/acs.accounts.1c00267
Self-Assembly of Ferritin: Structure, Biological Function and Potential Applications in Nanotechnology. Chakraborti Soumyananda,Chakrabarti Pinak Advances in experimental medicine and biology Protein cages are normally formed by the self-assembly of multiple protein subunits and ferritin is a typical example of a protein cage structure. Ferritin is a ubiquitous multi-subunit iron storage protein formed by 24 polypeptide chains that self-assemble into a hollow, roughly spherical protein cage. Ferritin has external and internal diameters of approximately 12 nm and 8 nm, respectively. Functionally, ferritin performs iron sequestration and is highly conserved in evolution. The interior cavity of ferritin provides a unique reaction vessel to carry out reactions separated from the exterior environment. In nature, the cavity is utilized for sequestration of iron and bio-mineralization as a mechanism to render iron inert and safe from the external environment. Material scientists have been inspired by this system and exploited a range of ferritin superfamily proteins as supramolecular templates to encapsulate different carrier molecules ranging from cancer drugs to therapeutic proteins, in addition to using ferritin proteins as well-defined building blocks for fabrication. Besides the interior cavity, the exterior surface and sub-unit interface of ferritin can be modified without affecting ferritin assembly. 10.1007/978-981-13-9791-2_10
Ferritin for the clinician. Knovich Mary Ann,Storey Jonathan A,Coffman Lan G,Torti Suzy V,Torti Frank M Blood reviews Ferritin, a major iron storage protein, is essential to iron homeostasis and is involved in a wide range of physiologic and pathologic processes. In clinical medicine, ferritin is predominantly utilized as a serum marker of total body iron stores. In cases of iron deficiency and overload, serum ferritin serves a critical role in both diagnosis and management. Elevated serum and tissue ferritin are linked to coronary artery disease, malignancy, and poor outcomes following stem cell transplantation. Ferritin is directly implicated in less common but potentially devastating human diseases including sideroblastic anemias, neurodegenerative disorders, and hemophagocytic syndrome. Additionally, recent research describes novel functions of ferritin independent of iron storage. 10.1016/j.blre.2008.08.001
Clinical thresholds for diagnosing iron deficiency: comparison of functional assessment of serum ferritin to population based centiles. Scientific reports Low serum ferritin is diagnostic of iron deficiency, yet its published lower cut-off values are highly variable, particularly for pediatric populations. Lower cut-off values are commonly reported as 2.5th percentiles, and is based on the variation of ferritin values in the population. Our objective was to determine whether a functional approach based on iron deficient erythropoiesis could provide a better alternative. Utilizing 64,443 ferritin test results from pediatric electronic health records, we conducted various statistical techniques to derive 2.5th percentiles, and also derived functional reference limits through the association between ferritin and erythrocyte parameters: hemoglobin, mean corpuscular volume, mean cell hemoglobin concentration, and red cell distribution width. We find that lower limits of reference intervals derived as centiles are too low for clinical interpretation. Functional limits indicate iron deficiency anemia starts to occur when ferritin levels reach 10 µg/L, and are largely similar between genders and age groups. In comparison, centiles (2.5%) presented with lower limits overall, with varying levels depending on age and gender. Functionally-derived limits better reflects the underlying physiology of a patient, and may provide a basis for deriving a threshold related to treatment of iron deficiency and any other biomarker with functional outcomes. 10.1038/s41598-020-75435-5
Adult-Onset Still's Disease: Clinical Aspects and Therapeutic Approach. Journal of clinical medicine Adult-onset Still's disease (AoSD) is a rare systemic autoinflammatory disease characterized by arthritis, spiking fever, skin rash and elevated ferritin levels. The reason behind the nomenclature of this condition is that AoSD shares certain symptoms with Still's disease in children, currently named systemic-onset juvenile idiopathic arthritis. Immune dysregulation plays a central role in AoSD and is characterized by pathogenic involvement of both arms of the immune system. Furthermore, the past two decades have seen a large body of immunological research on cytokines, which has attributed to both a better understanding of AoSD and revolutionary advances in treatment. Additionally, recent studies have introduced a new approach by grouping patients with AoSD into only two phenotypes: one with predominantly systemic features and one with a chronic articular disease course. Diagnosis presupposes an extensive diagnostic workup to rule out infections and malignancies. The severe end of the spectrum of this disease is secondary haemophagocytic lymphohistiocytosis, better known as macrophage activation syndrome. In this review, we discuss current research conducted on the pathogenesis, diagnosis, classification, biomarkers and complications of AoSD, as well as the treatment strategy at each stage of the disease course. We also highlight the similarities and differences between AoSD and systemic-onset juvenile idiopathic arthritis. There is a considerable need for large multicentric prospective trials. 10.3390/jcm10040733
Hyperferritinemia-A Clinical Overview. Sandnes Miriam,Ulvik Rune J,Vorland Marta,Reikvam Håkon Journal of clinical medicine Ferritin is one of the most frequently requested laboratory tests in primary and secondary care, and levels often deviate from reference ranges. Serving as an indirect marker for total body iron stores, low ferritin is highly specific for iron deficiency. Hyperferritinemia is, however, a non-specific finding, which is frequently overlooked in general practice. In routine medical practice, only 10% of cases are related to an iron overload, whilst the rest is seen as a result of acute phase reactions and reactive increases in ferritin due to underlying conditions. Differentiation of the presence or absence of an associated iron overload upon hyperferritinemia is essential, although often proves to be complex. In this review, we have performed a review of a selection of the literature based on the authors' own experiences and assessments in accordance with international recommendations and guidelines. We address the biology, etiology, and epidemiology of hyperferritinemia. Finally, an algorithm for the diagnostic workup and management of hyperferritinemia is proposed, and general principles regarding the treatment of iron overload are discussed. 10.3390/jcm10092008
The Role of NCOA4-Mediated Ferritinophagy in Ferroptosis. Advances in experimental medicine and biology Nuclear receptor coactivator 4 (NCOA4) is a selective cargo receptor that mediates the autophagic degradation of ferritin, the cytosolic iron storage complex, in a process known as ferritinophagy. NCOA4-mediated ferritinophagy is required to maintain intracellular and systemic iron homeostasis and thereby iron-dependent physiologic processes such as erythropoiesis. Given this role of ferritinophagy in regulating iron homeostasis, modulating NCOA4-mediated ferritinophagic flux alters sensitivity to ferroptosis, a non-apoptotic iron-dependent form of cell death triggered by peroxidation of polyunsaturated fatty acids (PUFAs). A role for ferroptosis has been established in the pathophysiology of cancer and neurodegeneration; however, the importance of ferritinophagy in these pathologies remains largely unknown. Here, we review the available evidence on biochemical regulation of NCOA4-mediated ferritinophagy and its role in modulating sensitivity to innate and induced ferroptosis in neurodegenerative diseases and cancer. Finally, we evaluate the potential of modulating ferritinophagy in combination with ferroptosis inducers as a therapeutic strategy. 10.1007/978-3-030-62026-4_4
Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis. Fuhrmann Dominik C,Mondorf Antonia,Beifuß Josefine,Jung Michaela,Brüne Bernhard Redox biology Cellular iron, at the physiological level, is essential to maintain several metabolic pathways, while an excess of free iron may cause oxidative damage and/or provoke cell death. Consequently, iron homeostasis has to be tightly controlled. Under hypoxia these regulatory mechanisms for human macrophages are not well understood. Hypoxic primary human macrophages reduced intracellular free iron and increased ferritin expression, including mitochondrial ferritin (FTMT), to store iron. In parallel, nuclear receptor coactivator 4 (NCOA4), a master regulator of ferritinophagy, decreased and was proven to directly regulate FTMT expression. Reduced NCOA4 expression resulted from a lower rate of hypoxic NCOA4 transcription combined with a micro RNA 6862-5p-dependent degradation of NCOA4 mRNA, the latter being regulated by c-jun N-terminal kinase (JNK). Pharmacological inhibition of JNK under hypoxia increased NCOA4 and prevented FTMT induction. FTMT and ferritin heavy chain (FTH) cooperated to protect macrophages from RSL-3-induced ferroptosis under hypoxia as this form of cell death is linked to iron metabolism. In contrast, in HT1080 fibrosarcome cells, which are sensitive to ferroptosis, NCOA4 and FTMT are not regulated. Our study helps to understand mechanisms of hypoxic FTMT regulation and to link ferritinophagy and macrophage sensitivity to ferroptosis. 10.1016/j.redox.2020.101670
Ferritin Metabolism Reflects Multiple Myeloma Microenvironment and Predicts Patient Outcome. International journal of molecular sciences Multiple myeloma (MM) is a hematologic malignancy with a multistep evolutionary pattern, in which the pro-inflammatory and immunosuppressive microenvironment and genomic instability drive tumor evolution. MM microenvironment is rich in iron, released by pro-inflammatory cells from ferritin macromolecules, which contributes to ROS production and cellular damage. In this study, we showed that ferritin increases from indolent to active gammopathies and that patients with low serum ferritin had longer first line PFS (42.6 vs. 20.7 months and, = 0.047, respectively) and OS (NR vs. 75.1 months and = 0.029, respectively). Moreover, ferritin levels correlated with systemic inflammation markers and with the presence of a specific bone marrow cell microenvironment (including increased MM cell infiltration). Finally, we verified by bioinformatic approaches in large transcriptomic and single cell datasets that a gene expression signature associated with ferritin biosynthesis correlated with worse outcome, MM cell proliferation, and specific immune cell profiles. Overall, we provide evidence of the role of ferritin as a predictive/prognostic factor in MM, setting the stage for future translational studies investigating ferritin and iron chelation as new targets for improving MM patient outcome. 10.3390/ijms24108852
Lactoferrin Binding to SARS-CoV-2 Spike Glycoprotein Blocks Pseudoviral Entry and Relieves Iron Protein Dysregulation in Several In Vitro Models. Pharmaceutics SARS-CoV-2 causes COVID-19, a predominantly pulmonary disease characterized by a burst of pro-inflammatory cytokines and an increase in free iron. The viral glycoprotein Spike mediates fusion to the host cell membrane, but its role as a virulence factor is largely unknown. Recently, the antiviral activity of lactoferrin against SARS-CoV-2 was demonstrated in vitro and shown to occur via binding to cell surface receptors, and its putative interaction with Spike was suggested by in silico analyses. We investigated the anti-SARS-CoV-2 activity of bovine and human lactoferrins in epithelial and macrophagic cells using a Spike-decorated pseudovirus. Lactoferrin inhibited pseudoviral fusion and counteracted the deleterious effects of Spike on iron and inflammatory homeostasis by restoring basal levels of iron-handling proteins and of proinflammatory cytokines IL-1β and IL-6. Using pull-down assays, we experimentally proved for the first time that lactoferrin binds to Spike, immediately suggesting a mechanism for the observed effects. The contribution of transferrin receptor 1 to Spike-mediated cell fusion was also experimentally demonstrated. In silico analyses showed that lactoferrin interacts with transferrin receptor 1, suggesting a multifaceted mechanism of action for lactoferrin. Our results give hope for the use of bovine lactoferrin, already available as a nutraceutical, as an adjuvant to standard therapies in COVID-19. 10.3390/pharmaceutics14102111
Iron promotes breast cancer cell migration via IL-6/JAK2/STAT3 signaling pathways in a paracrine or autocrine IL-6-rich inflammatory environment. Cheng Man,Liu Ping,Xu Lisa X Journal of inorganic biochemistry Iron overload can act as catalyst for the formation of free radicals, which may promote oxidant-mediated breast carcinogenesis. However, the association between iron and breast cancer has not been comprehensively elucidated. In this study, we found that iron overload upregulated the inflammatory cytokine interleukin-6 (IL-6) expression to activate Janus Kinases 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) signaling in triple negative breast cancer (TNBC) MDA-MB-231 cell lines, resulting in epithelial-mesenchymal transition (EMT) and cancer cell migration, but it had no effects on the estrogen receptor (ER)-positive breast cancer MCF-7 cells. However, in the presence of exogenous IL-6, iron overload could also dramatically induce an autocrine IL-6 loop in ER-positive MCF-7 cells to active IL-6/JAK2/STAT3 signaling, resulting in enhanced EMT and cell motility. In vivo animal studies also identified that iron overload promoted the progression of low metastatic breast cancer tumorigenicity and lung metastasis following the addition of exogenous IL-6. This study suggested that iron overload could result in inducible IL-6 expression leading to promote malignant transformation of breast cancer cells in an paracrine or autocrine IL-6-rich inflammatory environment. Anti-inflammation and iron depletion therapy would be an effective therapeutic/preventive strategy for suppressing breast cancer progression. 10.1016/j.jinorgbio.2020.111159
Protective effects of recombinant lactoferrin with different iron saturations on enteritis injury in young mice. Journal of dairy science Infant intestinal development is immature and, thus, is vulnerable to bacterial and viral infections, which damage intestinal development and even induce acute enteritis. Numerous studies have investigated that lactoferrin (LF) has protective effects on the intestine and may play a role in preventing intestinal inflammation in infants. Lactoferrin is divided into 2 types, namely apo-LF and holo-LF, depending on the degree of iron saturation, which may affect its bioactivities. However, the role of LF iron saturation in protecting infant intestinal inflammation has not been clearly clarified. Therefore, in this study, young mice models with intestinal damage induced by lipopolysaccharides (LPS) in vivo and primary intestinal epithelial cells in vitro were constructed to enteritis injury in infants for investigation. The apo-LF and holo-LF were subsequently applied to the mouse models to investigate and compare their levels of protection in the intestinal inflammatory injury, as well as to identify which LF was most active. Moreover, the specific mechanism of the LF with optimal iron saturation was further investigated through Western blot assay. Results demonstrated that disease activity index, shortened length of colon tissue, and histopathological score were significantly decreased in the apo-LF group compared with those of the LPS group and the holo-LF group. In the apo-LF group, the concentration of LPS in the intestinal tract and the number of gram-negative bacteria colonies decreased significantly and the expression levels of proinflammatory factors in the colon tissue were downregulated, in comparison with those in the LPS group. The findings of this study thus verify that apo-LF can significantly alleviate enteritis injury caused by LPS, through regulating the PPAR-γ/PFKFB3/NF-κB inflammatory pathway. 10.3168/jds.2021-21428
Serum GGT and serum ferritin as early markers for metabolic syndrome. Journal of family medicine and primary care BACKGROUND:In India, the prevalence of lifestyle diseases like diabetes, hypertension, and metabolic syndrome (MetS) is showing an upward trend. Gamma glutamate transferase (GGT) and ferritin increase oxidant stress in the body through their role in glutathione homeostasis and iron metabolism, respectively. The increase in oxidant stress increases the inflammatory load, a risk factor for metabolic syndrome. These parameters are cheap, patient-friendly, and available in routine diagnostic labs compatible for follow-up, relieving the already overburdened healthcare system. METHODOLOGY:In a case-control study, samples of 77 cases of metabolic syndrome and 77 age and sex-matched controls were analyzed for serum GGT (by modified IFCC) and serum ferritin (by CLIA). Statistical analysis was done by SPSS 20.0 version. RESULTS:The mean ± SD for ferritin and GGT were 101.58 ± 84.20 ng/dL and 36.67 ± 26.40 IU/L, respectively in cases, whereas in control group these values were 38.38 ± 29.26 ng/dL and 16.5 3 ± 6.79 IU/L ( < 0.001). Positive and significant correlation was seen between GGT with TG (r-value- 0.376/-value-0.001) and GGT with waist circumference (r-value- 0.298/-value- 0.022). A positive and significant correlation was seen between GGT and ferritin in cases with an r-value of 0.307 (-value - 0.01). CONCLUSION:The increased values of GGT and ferritin in cases suggest an inflammatory load. The positive and significant correlation between GGT and triglyceride indicates its role in increasing oxidants' stress leading to inflammation and the development of MetS. The association of ferritin with MetS though insignificant may be considered as a biomarker. 10.4103/jfmpc.jfmpc_570_20
Prognostic Value of Serum Iron, Ferritin, and Transferrin in Chronic Alcoholic Liver Disease. Ribot-Hernández Ivan,Martín-González Candelaria,Vera-Delgado Víctor,González-Navarrete Lourdes,de Armas-González José Fernando,Viña-Rodríguez José,Sánchez-Pérez María José,Rodríguez-Gaspar Melchor,González-Reimers Emilio Biological trace element research Ethanol increases iron absorption. Therefore, increased amount of iron reaches the liver, and exerts pro-oxidant effects and stimulates ferritin synthesis and hepatic stellate cell activation, promoting fibrosis and inflammation. These mechanisms would theoretically support a role of ferritin as a marker of the transition to liver cirrhosis, and, consequently, as a prognostic factor, but there is controversy regarding its behavior in alcoholics. We analyzed among 238 severe alcoholics the prognostic value of iron, ferritin, transferrin, transferrin saturation index (TSI) and total iron binding capacity (TIBC), and the relationships of these variables with liver function, proinflammatory markers (C-reactive protein (CRP), interleukin (IL)-6, IL-8, and tumor necrosis factor α), and the presence of cirrhosis. Patients showed higher serum ferritin (Z = 2.50, p = 0.031) but lower transferrin (t(264) = 4.81, p < 0.001), TIBC (t(262) = 4.44, p < 0.001), and iron (Z = 3.19, p = 0.001) values compared with 32 age- and sex-matched controls. Ferritin was related to inflammatory cytokines such as IL-8 (ρ = 0.18, p = 0.012) and to IL-6 (ρ = 0.16, p = 0.016), but not to liver function. On the contrary, cirrhotics showed lower transferrin (t(234) = 4.77, p < 0.001) and TIBC (t(232) = 4.67, p < 0.001), but higher TSI (Z = 3.35, p < 0.001) than non-cirrhotics. Transferrin, TSI, and TIBC were related to liver function impairment (marked differences among the Child's groups regarding transferrin (KW (2) = 22.83, p < 0.001), TSI (KW (2) = 15.81, p < 0.001), and TIBC (KW (2) = 21.38, p < 0.001) but only weakly to inflammation (inverse relationships between IL-6 and total iron (ρ = - 0.16, p = 0.017), TIBC (ρ = - 0.20, p = 0.002), and transferrin (ρ = - 0.20, p = 0.003). In accordance, albumin, IL-6, alcohol quitting, and TSI, in this order, were independently related to mortality, but not ferritin or iron. 10.1007/s12011-019-01887-0
Influence of Inflammation on Assessing Iron-Deficiency Anemia in Cuban Preschool Children. Pita-Rodríguez Gisela M,Chávez-Chong Cristina,Lambert-Lamazares Brenda,Montero-Díaz Minerva,Selgas-Lizano Rolando,Basabe-Tuero Beatriz,Alfonso-Sagué Karen,Díaz-Sánchez María E MEDICC review INTRODUCTION:Anemia is a public health problem worldwide and is most prevalent in preschool children, for whom it is the most frequent cause of nutritional deficits. In turn, iron deficiency is the main cause of anemia, affecting 43% of children globally. Previous studies in Cuba show rates of iron deficiency in preschool children between 38.6% and 57.6%, higher in infants (71.2% to 81.1%). WHO recommends using serum ferritin as an indicator of iron deficiency accompanied by acute (C-reactive protein) and chronic (a1-acid glycoprotein) inflammation biomarkers. OBJECTIVE:Assess how inflammation affects measuring and reporting of iron-deficiency anemia rates in Cuban preschool children. METHODS:Data were obtained from serum samples contained in the National Anemia and Iron Deficiency Survey, and included presumably healthy preschool Cuban children (aged 6-59 months). Serum samples were collected from 1375 children from randomly selected provinces in 4 regions of the country from 2014 through 2018. We examined the association between ferritin and two inflammatory biomarkers: C-reactive protein and a1-acid glycoprotein. Individual inflammation-adjusted ferritin concentrations were calculated using four approaches: 1) a higher ferritin cut-off point (⟨30 g/L); 2) exclusion of subjects showing inflammation (C-reactive protein ⟩5 mg/L or a1-acid glycoprotein ⟩1 g/L); 3) mathematical correction factor based on C-reactive protein or a1-acid glycoprotein; and 4) correction by regression with the method proposed by the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia Group. We estimated confidence intervals of differences between unadjusted prevalence and prevalence adjusted for inflammation by each method. RESULTS:The proportion of children with inflammation according to C-reactive protein concentrations >5 mg/L was lower (11.1%, 153/1375) than the proportion measured according to the concentrations of a1-acid glycoprotein, at >1 g/L (30.8%, 424/1375). The percentage of children with high concentrations of at least one of the aforementioned biomarkers was 32.7% (450/1375). Thus, each correction method increased the observed prevalence of iron deficiency compared to unadjusted estimates (23%, 316/1375). This increase was more pronounced when using the internal regression correction method (based only on C-reactive protein) or the method based on a higher cut-off point. Adjustment using all four methods changed estimated iron deficiency prevalence, increasing it from 0.1% to 8.8%, compared to unadjusted values. CONCLUSIONS:One-third of preschool children had biomarkers indicating elevated inflammation levels. Without adjusting for inflammation, iron deficiency prevalence was underestimated. The significant disparity between unadjusted and inflammation-adjusted ferritin when using some approaches highlights the importance of selecting the right approach for accurate, corrected measurement. The internal regression correction approach is appropriate for epidemiological studies because it takes into account inflammation severity. However, other models should be explored that account for inflammation and also provide better adjusted ferritin concentrations. 10.37757/MR2021.V23.N3.7
The many faces of transferrin: Does genotype modulate immune response? Kamińska-Gibas Teresa,Szczygieł Joanna,Jurecka Patrycja,Irnazarow Ilgiz Fish & shellfish immunology In this study, the expression of pro-inflammatory and iron metabolism genes were analysed under Trypanoplasma borreli (T. borreli) challenge in common carp. Three transferrin (Tf) genotypic groups: two homozygous - DD, GG, and heterozygous DG were intraperitoneally infected with a dose of 2.16 × 10/100 μL parasites. Organ and blood samples were collected at weekly intervals. During the infection period, mortality and parasitaemia were assessed along with measurements of blood iron concentrations and antibody levels. Expression of Tf, Fer, IRP1 and 2, TfR 1a and 1b, Hep, TNF α1 and α2, and IL-1 β was measured in the peak of parasitaemia and the week preceding the peak. Study revealed, that changes in iron blood level induced by parasite were not correlated with the activities of iron homeostasis genes. Neither iron content nor the specific antibody response correlated with survival. We demonstrate that challenged carp, display three distinct, Tf genotype dependent activity patterns of iron homeostasis genes expression. The expected, "classical" way of up-regulation represented homozygous DD individuals. In contrast, GG individuals demonstrated downward trend, while gene expressions of heterozygous DG carp could be defined as an intermediate. We speculate, whether this phenomenon is related to the transferrin molecule itself or to Tf-genotypes being markers of other factors, that influence the iron homeostasis genes activities. We discussed the role of alarmins in triggering the immune response. Distinct genes activating patterns of homozygous genotypes DD and GG had no consequences in terms of mortality rates caused by T.borreli. The highest mortality was observed in the heterozygous group DG. In conclusion, this study suggest that transferrin variant, but not iron blood concentration, has a significant impact on carp immune response to blood parasite infection. This research sheds a new light on the inflammation process and interaction between a host and invaders. 10.1016/j.fsi.2020.05.001
Early Testing of Serum Ferritin Facilitates Hemophagocytic Lymphohistiocytosis Diagnosis in Children. Agarwal Hemant S,Kuttesch John F Journal of pediatric hematology/oncology The clinical and laboratory features of hemophagocytic lymphohistiocytosis (HLH) are nonspecific that makes the definitive diagnosis of HLH very challenging. The disease is almost universally fatal in the absence of early recognition and appropriate therapy. Elevated serum ferritin level is one of the diagnostic markers of HLH disease. We report the value of testing serum ferritin level early in the disease process in 3 pediatric patients who presented with persistent fever and sepsis-like features. Detection of elevated serum ferritin levels facilitated further testing to confirm the diagnosis of HLH and initiate early therapy with good outcomes. 10.1097/MPH.0000000000001312
Secretion of von Willebrand Factor and Suppression of ADAMTS-13 Activity by Markedly High Concentration of Ferritin. Bashir Dalia A,Da Qi,Pradhan Subhashree,Sekhar Nitin,Valladolid Christian,Lam Fong,Guffey Danielle,Goldman Jordana,Desai Moreshwar S,Cruz Miguel A,Allen Carl,Nguyen Trung C,Vijayan K Vinod Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis Hyperferritinemia is associated with poor outcomes in critically ill patients with sepsis, hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndromes (MAS) and coronavirus disease 19 (COVID-19). Autopsies of hyperferritinemic patients that succumbed to either sepsis, HLH, MAS or COVID-19 have revealed disseminated microvascular thromboses with von Willebrand factor (VWF)-, platelets-, and/or fibrin-rich microthrombi. It is unknown whether high plasma ferritin concentration actively promotes microvascular thrombosis, or merely serves as a prognostic biomarker in these patients. Here, we show that secretion of VWF from human umbilical vein endothelial cells (HUVEC) is significantly enhanced by 100,000 ng/ml of recombinant ferritin heavy chain protein (FHC). Ferritin fraction that was isolated by size exclusion chromatography from the plasma of critically ill HLH patients promoted VWF secretion from HUVEC, compared to similar fraction from non-critically ill control plasma. Furthermore, recombinant FHC moderately suppressed the activity of VWF cleaving metalloprotease ADAMTS-13. These observations suggest that a state of marked hyperferritinemia could promote thrombosis and organ injury by inducing endothelial VWF secretion and reducing the ADAMTS-13 activity. 10.1177/1076029621992128
Ferritin Levels in Children With Sepsis in Low-Middle Income Countries: Do We Need Lower Threshold? Awasthi Pusp Raj,Angurana Suresh Kumar Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 10.1097/PCC.0000000000002443
Presepsin as a Novel Biomarker in predicting In-hospital Mortality in Patients With COVID-19 Pneumonia. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases OBJECTIVES:Different biomarkers such as C-reactive protein (CRP), serum ferritin and D-dimer are used in prognostic assessment of patients with COVID-19 pneumonia. Presepsin (PSP) is a soluble CD14 subtype that has recently been proposed as a novel biomarker in patients with sepsis. The aim of the current study was to detect the relation of PSP to the outcome of COVID-19 as well as its relation to other inflammatory biomarkers. METHODS:This multicenter retrospective observational study was conducted in Saudi Arabia and Misr International Hospital, Egypt, from January 2021 to May 2021. Hospitalised patients who had positive throat swab of SARS-CoV-2 and radiological evidence of viral pneumonia (moderate and severe forms) were included in the study. Demographics and clinical features, as well as laboratory parameters, including serum ferritin, CRP, D-dimer and PSP, of enrolled patients were retrospectively collected. Pneumonia severity index (PSI) was used to evaluate the severity of pneumonia. RESULTS:A total of 202 hospitalised patients who were diagnosed with COVID-19 pneumonia and tested positive for SARS-CoV-2 RNA were enrolled in our study. Of 202 hospitalised patients, 67 (33.17%) required intensive care unit (ICU) admission. A total of 176 (87.1%) patients survived and were discharged, whereas 26 (12.9%) patients did not survive. PSP level was found to be significantly elevated in nonsurvivor versus survivor group (median [IQR] 978.5 [755.8-1400] vs 516.5 [343.3-720], P<0.001) as well as in ICU versus non-ICU patients (median [IQR] 800 [631-1200] and 446 [320-626], respectively) (P<0.001). Elevated levels were also found to be associated with increased length of hospital stay. Levels above 775 pg/mL were found to be associated with in-hospital mortality (specificity 80%, sensitivity 73%). CONCLUSION:Elevated PSP levels indicated poor outcomes in hospitalised patients with COVID-19 pneumonia and were associated with in-hospital mortality. 10.1016/j.ijid.2022.02.054
Combination value of biomarkers in discriminating adult onset Still's disease and sepsis. Zhang Mengying,Xie Mengxiao,Wang Yaman,Li Jie,Zhou Jun Wiener klinische Wochenschrift BACKGROUND:Lymphocyte and plateletcrit (PCT) as proportions of routine complete blood count tests, have been studied as simple biomarkers for inflammatory diseases. The aim of our study was to investigate whether blood routine parameters, especially platelet parameters could be a useful tool to distinguish Adult onset Still's disease (AOSD) from sepsis. METHODS:We retrospectively reviewed 58 patients with AOSD and 55 sepsis patients diagnosed at the First Affiliated Hospital of Nanjing Medical University between January, 2015 to December 2018. Laboratory data including ferritin, blood routine parameters and C‑reactive protein (CRP) level were collected, and the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte (PLR) were calculated. RESULTS:The results showed that AOSD patients showed higher ferritin, lymphocyte and PCT (all P < 0.01) and these factors are independent risk factors for predicting AOSD. In receiver operating characteristic (ROC) curve analysis of LY, PCT and ferritin for distinguish of AOSD, the area under the curve (AUC) was 0.676 (0.576-0.777); 0.706 (95% CI = 0.596-0.816); 0.715 (0.617-0.814). Meanwhile, the AUC of the combination of lymphocyte, PCT and ferritin was 0.836 (0.737-0.909) with sensitivity 67.3, specificity 92.3, and the difference was significant. CONCLUSIONS:Thus we suggest that lymphocyte, PCT may be a useful tool to make a distinction between AOSD and sepsis, as supplementary biomarkers to ferritin. 10.1007/s00508-020-01668-z
Association between heme oxygenase one and sepsis development in patients with moderate-to-critical COVID-19: a single-center, retrospective observational study. European journal of medical research BACKGROUND:Heme oxygenase one (HO-1) is considered a poor prognostic factor for survival in patients with severe-to-critical coronavirus disease (COVID-19), but the clinical correlation between heme catabolism biomarkers and COVID-19-related sepsis is unknown. The etiopathogenetic hypothesis of HO-1 response during sepsis in patients with poor prognosis should be clarified. This study aimed to investigate sepsis development within 48 h following moderate-to-critical COVID-19 and examined heme/HO-1 catabolism biomarkers associated with sepsis. We also studied the HO-1 and traditional prognostic factors for predicting survival in patients with COVID-19. METHODS:This retrospective observational study included patients unvaccinated for COVID-19 with moderate-to-critical COVID-19 (n = 156) who had been admitted to Taipei Tzu Chi Hospital in 2021. All COVID-19 patients were diagnosed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase polymerase chain reaction. For analysis of heme catabolism in SARS-CoV-2-induced sepsis, we excluded patients with co-infection and severe anemia. Heme catabolism biomarkers were compared between groups of patients with COVID-19 and sepsis (sepsis) and those with COVID-19 without sepsis (no sepsis), and a control group comprising 100 healthy individuals. All clinical and laboratory data were collected retrospectively and blood specimens were collected from Biobank. Multivariable logistic regression analysis was used to compare all variables between the sepsis and no-sepsis groups. Cox regression analysis was used to determine predictors of survival in patients with COVID-19. RESULTS:There were 71 and 85 patients with and without sepsis, respectively. Heme and HO-1 levels differed significantly between the sepsis, no sepsis, and control groups. In multivariate analysis, confusion, blood urea nitrogen, respiration, blood pressure in patients aged > 65 years (CURB-65) (adjusted odds ratio [aOR] 5.331, 95% confidence interval [CI] 2.587-10.987; p < 0.001), albumin (aOR 0.139, 95% CI 0.003-0.636; p = 0.01), D-dimer (aOR 1.001, 95% CI 1.000-1.002; p = 0.032), and HO-1 (aOR 1.116, 95% CI 1.055-1.180; p < 0.001) were significantly associated with 48-h sepsis episodes after adjusting for other confounding factors. HO-1 levels were also significantly associated with 48-h Sequential Organ Failure Assessment Score (SOFA) scores. However, HO-1 did not significantly increase the hazard of in-hospital mortality in moderate-to-critical COVID-19 by Cox regression analysis. CONCLUSIONS:HO-1 levels increased with sepsis development within 48 h of admission for COVID-19 after adjusting for other risk factors, but no significant association was observed between HO-1 and COVID-19 mortality. We suppose that HO-1 may have protective effect in early sepsis, but further clinical multicenter prospective studies are needed. 10.1186/s40001-022-00915-5
Serum ferritin in neonatal cholestasis: A specific and active molecule or a non-specific bystander marker? Behairy Behairy El-Sayed,Konswa Hatem Abd-Alsattar,Ahmed Hanaa Talaat,El-Azab Dina Shehata,Adawy Nermin Mohamed,Sira Ahmad Mohamed Hepatobiliary & pancreatic diseases international : HBPD INT BACKGROUND:Serum ferritin (SF) and consequently hepatic iron have long been considered important in liver fibrosis progression. They have been studied in different liver diseases with no previous reports in neonatal cholestasis (NC). This study aimed to measure SF in different etiologies of NC and investigate its relation to hepatic iron and fibrosis. METHODS:SF was measured in 75 infants, including 50 with NC and 25 with sepsis. SF was compared between these two groups. Biochemical parameters, hepatic iron grades, and liver fibrosis and other histopathological characteristics and correlated with SF were assessed in NC group. Finally, a comparison between intrahepatic cholestasis and obstructive etiology was performed. RESULTS:SF was elevated in NC (1598 ± 2405 ng/mL) with no significant difference from those with sepsis (P = 0.445). NC and sepsis constituted augmenting factors leading to more elevation of SF (2589 ± 3511 ng/mL). SF was significantly correlated with hepatic iron grades (r = 0.536, P < 0.0001) and a cut-off value of 803.5 ng/mL can predict higher grades (≥ grade 3) of iron deposition with sensitivity of 100%, specificity of 70% and accuracy of 85%. Moreover, SF was significantly higher (P < 0.0001) in those with intrahepatic cholestasis (2602 ± 3154 ng/mL) and their prevalent pathological findings of giant cell transformation (P = 0.009) and hepatocyte swelling (P = 0.023) than those with obstructive etiology (672 ± 566 ng/mL) and their prevalent pathological findings of ductular proliferation (P = 0.003) and bile plugs (P = 0.002). SF was unrelated to the grade of liver fibrosis (P = 0.058). CONCLUSIONS:SF is non-specifically elevated in NC, with positive correlation to hepatic iron grades. SF ≥ 803.5 ng/mL can predict higher grades (≥ grade 3) of hepatic iron. However, an active role of increased SF and hepatic iron in disease progression remains questionable. 10.1016/j.hbpd.2019.02.006
Elevated ferritin and soluble CD25 in critically ill patients are associated with parameters of (hyper) inflammation and lymphocyte cytotoxicity. von Bahr Greenwood Tatiana,Palmkvist-Kaijser Kajsa,Chiang Samuel C,Tesi Bianca,Bryceson Yenan T,Hjelmqvist Hans,Henter Jan-Inge Minerva anestesiologica BACKGROUND:Critically ill patients may develop a potentially fatal hyperinflammatory condition known as secondary (acquired) hemophagocytic lymphohistiocytosis (sHLH), the cause of which is unclear. We evaluated serum ferritin and soluble CD25 (sCD25) in critically ill patients, and their association with other parameters of inflammation and critical illness. Moreover, aiming to better understand the pathogenesis of sHLH, we also evaluated lymphocyte cytotoxicity parameters and correlations with the inflammatory markers ferritin and sCD25. METHODS:In a prospective observational study, 32 patients with ferritin ≥500 µg/L (24 with sepsis) were studied on admission to an intensive care unit (ICU) with regard to ferritin and corresponding clinical and laboratory features including sCD25, and detailed lymphocyte cytotoxicity and genetic analyses whenever possible. RESULTS:Critically ill patients had elevated, positively correlated levels of serum ferritin and sCD25 (rs=0.465, P=0.008); both associated with other risk factors of poor outcome in critically ill, such as thrombocytopenia (rs=-0.534, P=0.002 and rs=-0.421, P=0.018, respectively), and sCD25 with hypoalbuminemia (rs=-0.678, P<0.001) and life support treatments (rs=0.479, P=0.006). Interestingly, ferritin levels were inversely associated with natural killer (NK)-cell cytotoxicity (rs=-0.462, P=0.047) and degranulation (rs=-0.504, P=0.030). Moreover, of four patients with abnormally low cytotoxicity, three (75%) had <5% circulating NK-cells. CONCLUSIONS:Our study suggests that hyperferritinemia and sCD25 correlate with other laboratory parameters indicative of severe hyperinflammation and organ dysfunction in critically ill ICU-patients, indicating their value in identifying hyperinflammatory critically ill patients for early intervention. Furthermore, it suggests that hyperferritinemia and hyperinflammation may partly be associated with a low percentage circulating NK-cells, and hence, the associated low lymphocyte cytotoxicity. 10.23736/S0375-9393.19.13534-1
Iron status and the risk of sepsis and severe COVID-19: a two-sample Mendelian randomization study. Scientific reports 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. 10.1038/s41598-022-20679-6
Ferritin modifies the relationship between inflammation and arterial stiffness in hypertensive patients with different glucose tolerance. Cardiovascular diabetology BACKGROUND:Ferritin, a crucial element for iron homeostasis, is associated with chronic diseases characterized by subclinical inflammation such as essential arterial hypertension and type 2 diabetes mellitus (T2DM), showing a prognostic value in different clinical settings. We investigated whether ferritin is associated with arterial stiffness (AS), an early indicator of atherosclerosis, and if it could act as effect modifier on the relationship between inflammation and AS in hypertensive patients with different glucose tolerance. METHODS:We enrolled 462 newly diagnosed untreated hypertensive (HT) patients. All subjects underwent an oral glucose tolerance test. Insulin sensitivity was assessed by MATSUDA index and ferritin levels were estimated by immunoradiometric assay. AS was defined by carotid-femoral pulse wave velocity (PWV). RESULTS:Out of 462 patients, 271 showed normal glucose tolerance (HT/NGT), 146 impaired glucose tolerance (HT/IGT) and 45 were diabetic (HT/T2DM). Iron levels significantly decreased and transferrin and ferritin significantly increased from the first to the third group. PWV values were significantly higher in HT/IGT and HT/T2DM patients. PWV was related directly with ferritin, high sensitivity C reactive protein (hs-CRP), transferrin, and inversely with MATSUDA index. Ferritin resulted the strongest determinant of PWV explaining a 14.9% of its variation; moreover it was a strong modifier of the relationship between hs-CRP and PWV. The estimated augmentation in PWV portended by a fixed increase in hs-CRP, was higher across increasing values of ferritin. CONCLUSION:Ferritin represents an independent risk factor of arterial stiffness in our study population and a strong effect modifier on the relationship between inflammation and PWV. However, further studies are needed to fully elucidate the potential role of this biomarker in human atherosclerosis. 10.1186/s12933-020-01102-8
Ascorbate and ferritin interactions: Consequences for iron release in vitro and in vivo and implications for inflammation. Badu-Boateng Charles,Naftalin Richard J Free radical biology & medicine This review discusses the chemical mechanisms of ascorbate-dependent reduction and solubilization of ferritin's ferric iron core and subsequent release of ferrous iron. The process is accelerated by low concentrations of Fe(II) that increase ferritin's intrinsic ascorbate oxidase activity, hence increasing the rate of ascorbate radical formation. These increased rates of ascorbate oxidation provide reducing equivalents (electrons) to ferritin's core and speed the core reduction rates with subsequent solubilization and release of Fe(II). Ascorbate-dependent solubilization of ferritin's iron core has consequences relating to the interpretation of Fe uptake sourced from Fe-lebelled holotransferrin into ferritin. Ascorbate-dependent reduction of the ferritin core iron solubility increases the size of ferritin's iron exchangeable pool and hence the rate and amount of exchange uptake of Fe into ferritin, whilst simultaneously increasing net iron release rate from ferritin. This may rationalize the inconsistency that ascorbate apparently stabilizes Fe ferritin and retards lysosomal ferritinolysis and whole cell Fe release, whilst paradoxically increasing the rate of net iron release from ferritin. This capacity of ascorbate and iron to synergise ferritin iron release has pathological significance, as it lowers the concentration at which ascorbate activates ferritin's iron release to within the physiological range (50-250 μM). These effects have relevance to inflammatory pathology and to the pro-oxidant effects of ascorbate in cancer therapy and cell death by ferroptosis. 10.1016/j.freeradbiomed.2018.09.041
Ferritin, sex, and the wildfire of inflammation in Hodgkin lymphoma. Leukemia & lymphoma 10.1080/10428194.2022.2034161
Ferritin triggers neutrophil extracellular trap-mediated cytokine storm through Msr1 contributing to adult-onset Still's disease pathogenesis. Nature communications Hyperferritinemic syndrome, an overwhelming inflammatory condition, is characterized by high ferritin levels, systemic inflammation and multi-organ dysfunction, but the pathogenic role of ferritin remains largely unknown. Here we show in an animal model that ferritin administration leads to systemic and hepatic inflammation characterized by excessive neutrophil leukocyte infiltration and neutrophil extracellular trap (NET) formation in the liver tissue. Ferritin-induced NET formation depends on the expression of peptidylarginine deiminase 4 and neutrophil elastase and on reactive oxygen species production. Mechanistically, ferritin exposure increases both overall and cell surface expression of Msr1 on neutrophil leukocytes, and also acts as ligand to Msr1 to trigger the NET formation pathway. Depletion of neutrophil leukocytes or ablation of Msr1 protect mice from tissue damage and the hyperinflammatory response, which further confirms the role of Msr1 as ferritin receptor. The relevance of the animal model is underscored by the observation that enhanced NET formation, increased Msr1 expression and signalling on neutrophil leukocytes are also characteristic to adult-onset Still's disease (AOSD), a typical hyperferritinemic syndrome. Collectively, our findings demonstrate an essential role of ferritin in NET-mediated cytokine storm, and suggest that targeting NETs or Msr1 may benefit AOSD patients. 10.1038/s41467-022-34560-7
Chemistry and biology of ferritin. Plays Marina,Müller Sebastian,Rodriguez Raphaël Metallomics : integrated biometal science Iron is an essential element required by cells and has been described as a key player in ferroptosis. Ferritin operates as a fundamental iron storage protein in cells forming multimeric assemblies with crystalline iron cores. We discuss the latest findings on ferritin structure and activity and its link to cell metabolism and ferroptosis. The chemistry of iron, including its oxidation states, is important for its biological functions, its reactivity, and the biology of ferritin. Ferritin can be localized in different cellular compartments and secreted by cells with a variety of functions depending on its spatial context. Here, we discuss how cellular ferritin localization is tightly linked to its function in a tissue-specific manner, and how impairment of iron homeostasis is implicated in diseases, including cancer and coronavirus disease 2019. Ferritin is a potential biomarker and we discuss latest research where it has been employed for imaging purposes and drug delivery. 10.1093/mtomcs/mfab021
Ferritin and Hemoglobin as Predictors of Fatal Outcome in COVID-19: Two Sides of the Same Coin. Raman Nishant,Kv Padmaprakash,Ashta Kuldeep Kumar,Vardhan Vasu,Thareja Sandeep,J Muthukrishnan,Kumar Abhinav,Basavaraj The Journal of the Association of Physicians of India INTRODUCTION:Infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have multisystemic involvement with hyperinflammation being a cardinal feature and deranged iron metabolism having a possible role. In this premise, we studied the prognostic value of two markers of iron metabolism ferritin and hemoglobin. METHODOLOGY:A retrospective-cohort study was carried out in a tertiary hospital in northern India involving 210 hospitalized COVID-19 patients aged 15-and above. Analysis was done for clinical profile, comorbidities and basic laboratory indices including ferritin-hemoglobin ratio (FHR) with primary end-point being in-hospital all-cause mortality. RESULTS:Median serum ferritin levels (640.00ng/mL vs 220.00ng/mL) were significantly higher among non-survivors as against survivors while median hemoglobin levels were significantly lower (12.12g/dL vs 13.73g/dL). Serum ferritin levels &gt;400ng/mL (Sn 80%, Sp 70%) predicted mortality with high sensitivity and specificity. Notably, serum ferritin levels &gt;400ng/mL (HR 11.075 [1.481-82.801]) and anemia, defined as a hemoglobin of &lt;12g/dL for females and &lt; 13g/dL for males and were significantly associated with the risk of mortality in a univariable Cox-proportional hazards regression. The median FHR was significantly higher among non-survivors compared to survivors (56.98 vs 17.17). FHR&gt;31 (Sn 85% Sp 71.6%) was highly sensitive and specific for predicting mortality. The multivariable analysis indicated that FHR &gt;31 remained an independent risk factor for mortality (HR 12.293 [3.147-48.028]). CONCLUSION:Ferritin-hemoglobin ratio (FHR), which encompasses into a single index, the effects of both elevated levels of ferritin and the severity of anemia, seems to perform particularly well as a prognostic marker and emerged as an independent risk factor for mortality in COVID-19 patients. Hyperferritinemia and anemia, both, are inexorably interlinked in addition to having a role, directly or indirectly in the disease pathophysiology. Ferritin and hemoglobin, hence should be seen as two sides of the same coin rather than as two discrete entities.
Could ferritin level be an indicator of COVID-19 disease mortality? Journal of medical virology While the number of coronavirus disease-2019 (COVID-19) cases is increasing day by day, there is limited information known about the hematological and laboratory findings of the disease. We aimed to investigate whether serum ferritin level predicts mortality is a marker for rapid progression for inpatients. Our study included 56 patients who were died due to COVID-19 as the study group, and 245 patients who were hospitalized and recovered as the control group. The laboratory data of the patients were evaluated from the first blood tests (pre) taken from the first moment of admission to the hospital and the blood tests taken from before the patient's discharge or exitus (post) were evaluated retrospectively. The mean age of the nonsurvivor group was 62.0 ± 15.7 and the mean age of the control group was 54.34 ± 13.03. Age and length of stay are significantly higher in the nonsurvivor group. When comparing the pre- and postvalues of ferritin, according to the two groups separately, there was no significant difference in the control group and a high level of significance was observed in the nonsurvivor group (p < .01). COVID-19 disease caused by severe acute respiratory syndrome coronavirus-2 causes high mortality with widespread inflammation and cytokine storm. Ferritin is a cheap and widespread available marker, ferritin, which can be used for its predictivity of the mortality and hope it would be a useful marker for clinicians for the management of the disease. 10.1002/jmv.26543
Clinical and prognostic significance of elevated ferritin levels in hospitalised adults. Postgraduate medical journal PURPOSE OF THE STUDY:Elevated ferritin levels are associated with a variety of infectious, malignant and inflammatory diseases. We aimed to investigate the prognostic value of markedly elevated ferritin levels in hospitalised patients with various medical conditions. STUDY DESIGN:Retrospective analysis of patients with a ferritin level higher than 2000 ng/mL hospitalised in Sheba Medical Center between 1 January 2007 and 31 December 2015. Medical conditions of these patients were recorded. In-hospital, 30-day and 1-year mortality rates were evaluated according to ferritin ranges and clinical categories. RESULTS:The study included 722 patients (63.4% men) with a mean age of 63.9±16.7 years. The most common clinical conditions associated with markedly elevated ferritin were infectious diseases and malignancies. The highest mean ferritin levels were associated with rheumatological/inflammatory conditions (16 241.3 ng/dL), particularly in patients with macrophage activation syndrome (MAS) (96 615.5 ng/dL). In-hospital, 30-day and 1-year mortality rates were 32.3%, 46.7% and 70.8%, respectively. The highest in-hospital, 30-day and 1-year mortality rates were observed among patients with solid malignancies (40.1%, 64.7% and 90.3%, respectively), whereas the lowest rates were found among patients with rheumatological/inflammatory conditions, including MAS (21.4%, 38.1% and 45.2%, respectively). Ferritin levels were not associated with mortality. CONCLUSIONS:In hospitalised patients, ferritin levels higher than 2000 ng/mL are mainly associated with infectious and malignant diseases but do not predict mortality. 10.1136/postgradmedj-2021-139832
Systemic inflammation modulates the ability of serum ferritin to predict all-cause and cardiovascular mortality in peritoneal dialysis patients. BMC nephrology BACKGROUND:This study aimed to ascertain whether the correlation of high serum ferritin with mortality is affected by systemic inflammation and to investigate the optimal serum ferritin level for predicting death when inflammation is considered in peritoneal dialysis (PD) patients. METHODS:We classified 221 patients into four groups according to serum ferritin concentration (100 μg/L) and high-sensitivity CRP (hs-CRP) level (3 mg/L), and followed them regularly from the date of catheterization to Dec 31, 2016, at Sun Yat-Sen Memorial Hospital, China. Clinical and biochemical data were collected at baseline, and clinical outcomes such as all-cause and cardiovascular mortality were assessed. RESULTS:During a median follow-up of 35 months (3 ~ 109 months), 50 (22.6%) deaths occurred. Cardiovascular disease (46.0%) was the most common cause of death, followed by infection (10.0%). The Kaplan-Meier survival analysis and log-rank test revealed significantly worse survival accumulation among PD patients with higher serum ferritin (≥100 μg/L) under elevated hsCRP levels (> 3 mg/L) (P = 0.022). A multivariate Cox regression analysis revealed that an increased serum ferritin level was independently associated with a higher risk of all-cause and cardiovascular mortality in PD patients (HR = 3.114, P = 0.021; and HR = 9.382, P = 0.032) with hsCRP above 3 mg/L after adjusting for relevant confounding factors. CONCLUSION:Higher serum ferritin levels were associated with an increased risk of all-cause and cardiovascular mortality in patients undergoing PD only in the presence of elevated hsCRP levels. The correlation of serum ferritin with poor outcome should take into consideration systemic inflammation. 10.1186/s12882-020-01892-9
Serum levels of ferritin and transferrin serve as prognostic factors for mortality and survival in patients with end-stage liver disease: A propensity score-matched cohort study. Meier Jörn Arne,Bokemeyer Arne,Cordes Friederike,Fuhrmann Valentin,Schmidt Hartmut,Hüsing-Kabar Anna,Kabar Iyad United European gastroenterology journal BACKGROUND:Patients with end-stage liver disease are known to suffer from a significantly high risk of mortality, but accurate prediction of the course of disease is challenging. OBJECTIVE:The study aim was to evaluate the independent prognostic and clinical importance of serum levels of ferritin and transferrin for 90-day survival of patients with liver disease. METHODS:Patients with end-stage liver disease treated during a 2-year period were enrolled retrospectively in a single-centre study. Unmatched and propensity score matching (PSM) analyses were applied. RESULTS:The study cohort comprised 286 patients with end-stage liver disease, of which 22.9% died during the observational period. High serum ferritin levels and low serum transferrin levels were associated significantly with increased 90-day mortality in the unmatched ( < 0.001) and PSM study population ( = 0.017). Serum levels of ferritin and transferrin had high prognostic capability to predict 90-day survival similar to the Model for End-stage Liver Disease. Patients with serum ferritin values >1030.5 µg/l had a 50% risk of dying within 11 days after measurement, which translated up to a 90-day mortality of 83%. CONCLUSION:Serum levels of ferritin and transferrin have independent and excellent capabilities to determine prognosis in patients with end-stage liver disease. Ferritin measurements can reliably identify those with high mortality in daily practice. 10.1177/2050640619891283
The Importance of D-Dimer, Ferritin, CRP and Lymphocyte Values in Determining Mortality in COVID-19 Disease in Turkey. Clinical laboratory BACKGROUND:It is critical to determine the importance of laboratory tests on the mortality of Covid-19 disease. Our aim is to search the effect of D-dimer, C-reactive protein (CRP), ferritin, and lymphocyte count in the algorithm organized by our Ministry of Health in the diagnosis and treatment of Covid-19 on mortality. METHODS:Two hundred forty-five patients admitted to the emergency department (ED) with a diagnosis of Covid-19 pneumonia between March 15, 2020, and May 15, 2020. CRP, D-dimer, ferritin, and lymphocyte count included in the algorithm of the Ministry of Health. The relationship between demographic, clinical, and laboratory characteristics of the patients and their thirty-day mortality was examined. RESULTS:A statistically significant difference was only found in coronary artery disease between the mortality rates and underlying diseases of the patients included in the study. When the diagnostic contribution of laboratory values to the mortality estimation was evaluated, the areas under the curve were the highest for CRP 0.782 (95% Cl 0.68 - 0.88), ferritin 0.740 (95% Cl 0.60 - 0.88), and D-dimer 0.738 (95% Cl 0.58 - 0.89). CONCLUSIONS:An increased serum CRP, D-dimer, ferritin levels, and low lymphocyte count as shown by Turkish Ministry of Health in Turkey are significant predictors of COVID-19 mortality. 10.7754/Clin.Lab.2021.210720
Ferritin levels in patients with COVID-19: A poor predictor of mortality and hemophagocytic lymphohistiocytosis. Feld Jonathan,Tremblay Douglas,Thibaud Santiago,Kessler Alaina,Naymagon Leonard International journal of laboratory hematology INTRODUCTION:A hyperinflammatory environment has been a hallmark of COVID-19 infection and is thought to be a key mediator of morbidity. Elevated ferritin has been observed in many patients with COVID-19. Several retrospective studies have shown ferritin levels can be correlated and predictive of poor outcomes in COVID-19, though a rigorous analysis has been lacking. METHODS:A retrospective analysis of 942 adult COVID-19 patients admitted in March 2020 at a large New York City health system with available ferritin levels. RESULTS:The primary outcome, all-cause mortality, was observed in 265 (28.1%) patients. Patients who died had a significantly higher median admission and maximum ferritin levels than those who did not. However, death was poorly predicted by admission and maximum ferritin levels on receiver operator curve (ROC) analysis, with AUCs of 0.677 and 0.638, respectively. AUCs increased when the cohort was limited to progressively younger patients. Ferritin levels were minimally better at predicting our secondary outcomes. These included mechanical ventilation, observed in 280 (29.7%) patients with an ROC yielding an area under the curve (AUC) of 0.769, and new renal replacement therapy, observed in 80 (8.5%) of patients with an ROC yielding an AUC of 0.787. We also performed a subset analysis on 22 patients with ferritins >20 000 ng/mL. None of the patients met HLH-2004 diagnostic criteria. Fifteen (68.2%) of these patients had suspected or confirmed bacterial infections. CONCLUSIONS:Though many patients with COVID-19 present with hyperferritinemia, elevated ferritin levels are not accurate predictors of outcomes and do not appear to be indicative of hemophagocytic lymphohistiocytosis. 10.1111/ijlh.13309
Ferritin and C-reactive protein are predictive biomarkers of mortality and macrophage activation syndrome in adult onset Still's disease. Analysis of the multicentre Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort. Di Benedetto Paola,Cipriani Paola,Iacono Daniela,Pantano Ilenia,Caso Francesco,Emmi Giacomo,Grembiale Rosa Daniela,Cantatore Francesco Paolo,Atzeni Fabiola,Perosa Federico,Scarpa Raffaele,Guggino Giuliana,Ciccia Francesco,Giacomelli Roberto,Ruscitti Piero PloS one OBJECTIVE:To assess the predictive role of ferritin and C-reactive protein (CRP) on occurrence of macrophage activation syndrome (MAS) and mortality in patients with adult onset Still's disease (AOSD), a rare and severe disease, included in the multicentre Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort. METHODS:The predictive role, at the time of diagnosis, of serum levels of ferritin and CRP on occurrence of MAS and mortality, was evaluated by logistic regression analyses and receiver-operating characteristic (ROC) curves were built to identify patients at high risk of MAS and mortality, respectively. RESULTS:In assessed 147 patients with AOSD, levels of ferritin were predictive of MAS (OR: 1.971; P: 0.002; CI 95%: 1.280-3.035). The ROC curve showed that the best cut-off for ferritin was 1225 ng/ml in predicting MAS (sensitivity 88%; specificity 57%). Levels of CRP were predictive of mortality in these patients (OR: 2.155; P: 0.007; CI 95%: 1.228-3.783). The ROC curve showed that the best cut-off for CRP was 68.7 mg/L in predicting mortality (sensitivity 80%; specificity of 65%). CONCLUSIONS:We reported the predictive role of ferritin and CRP on MAS and mortality, respectively, in a large cohort of patients with AOSD, identifying subsets at higher risk of poor prognosis. Considering that the analysis of CRP and ferritin is widely available, these results could be readily transferable into clinical practice, thus improving the management of patients with AOSD. 10.1371/journal.pone.0235326
Evaluation of serum ferritin for prediction of severity and mortality in COVID-19- A cross sectional study. Ahmed Sibtain,Ansar Ahmed Zeeshan,Siddiqui Imran,Haroon Rashid Naveed,Mansoor Maheen,Jafri Lena Annals of medicine and surgery (2012) Background:Ferritin even though widely recognized as a representative of total body iron stores, its prognostic utility is linked with COVID-19. This study was aimed at evaluation of the association of ferritin with severity in Coronavirus disease 2019 (COVID-19), hospitalized patients and to test the hypothesis that it is an independent predictor of mortality. Material and methods:This study was conducted at Chemical Pathology, Department of Pathology and Laboratory Medicine, Aga Khan University (AKU), Karachi. Medical records of all in-patients including both genders, and all age groups with documented COVID-19 from 1st March to 10 August 2020 were reviewed. The subjects were divided into two categories severe and non-severe COVID-19; and survivors and non-survivors. The details were recorded on a pre-structured performa. Between-group differences were tested using the Mann-Whitney's -test. The receiver operating characteristic curve was plotted for ferritin with severity and mortality. A binary logistic regression was used to identify variables independently associated with mortality. The data was analyzed using Statistical Package for the Social Sciences (SPSS) Results:A total of 336 in patients were reviewed as declared COVID-19 positive during the study duration, and 157 were included in the final analysis including 108 males and 49 females. Statistically significant difference in ferritin was found in the two categories based on severity and mortality. Binary logistic regression showed ferritin to be an independent predictor of all-cause mortality supplemented with an AUC of 0.69 on ROC analysis. Conclusions:Serum ferritin concentration is a promising predictor of mortality in COVID-19 cases. 10.1016/j.amsu.2021.02.009
Ferritin level: A predictor of severity and mortality in hospitalized COVID-19 patients. Immunity, inflammation and disease INTRODUCTION:This study aims to investigate in-hоsрitаl mоrtаlity in severe асute resрirаtоry syndrоme соrоnаvirus 2 раtients strаtified by serum ferritin levels. METHODS:Patients were stratified based on ferritin levels (ferritin levels ≤ 1000 or >1000). RESULTS:Approximately 89% (118) of the patients with ferritin levels > 1000 had pneumonia, and 51% (67) had hypertension. Fever (97, 73.5%) and shortness of breath (80, 61%) were two major symptoms among the patients in this group. Logistic regression analysis indicated that ferritin level (odds ratio [OR] = 0.36, 95% confidence interval [CI] = 0.21-0.62; p < .001), male sex (OR = 2.63, 95% CI = 1.43-5.06; p = .003), hypertension (OR = 4.16, 95% CI = 2.42-7.36; p < .001) and pneumonia (OR = 8.48, 95% CI = 3.02-35.45; p < .001) had significance in predicting in-hospital mortality. Additionally, the Cox proportional hazards analysis and Kaplan-Meier survival probability plot showed a higher mortality rate among patients with ferritin levels > 1000. CONCLUSION:In this study, higher levels of serum ferritin were found to be an independent predictor of in-hоsрitаl mоrtаlity. 10.1002/iid3.517
The Relationship between Serum Ferritin Levels and 5-Year All-Cause Mortality in Hemodialysis Patients. Erdem Emre,Karatas Ahmet,Ecder Tevfik Blood purification INTRODUCTION:The effect of high serum ferritin levels on long-term mortality in hemodialysis patients is unknown. The relationship between serum ferritin levels and 5-year all-cause mortality in hemodialysis patients was investigated in this study. METHODS:A total of 173 prevalent hemodialysis patients were included in this study. The patients were followed for up to 5 years and divided into 3 groups according to time-averaged serum ferritin levels (group 1: serum ferritin <800 ng/mL, group 2: serum ferritin 800-1,500 ng/mL, and group 3: serum ferritin >1,500 ng/mL). Along with the serum ferritin levels, other clinical and laboratory variables that may affect mortality were also included in the Cox proportional-hazards regression analysis. RESULTS:Eighty-one (47%) patients died during the 5-year follow-up period. The median follow-up time was 38 (17.5-60) months. The 5-year survival rates of groups 1, 2, and 3 were 44, 64, and 27%, respectively. In group 3, the survival was lower than in groups 1 and 2 (log-rank test, p = 0.002). In group 1, the mortality was significantly lower than in group 3 (HR [95% CI]: 0.16 [0.05-0.49]; p = 0.001). In group 2, the mortality was also lower than in group 3 (HR [95% CI]: 0.32 [0.12-0.88]; p = 0.026). No significant difference in mortality between groups 1 and 2 was found (HR [95% CI]: 0.49 [0.23-1.04]; p = 0.063). CONCLUSION:Time-averaged serum ferritin levels >1,500 ng/mL in hemodialysis patients are associated with an increased 5-year all-cause mortality risk. 10.1159/000515639
Association of ferritin and transferrin saturation with all-cause mortality, and the effect of concurrent inflammation: a danish cohort study. Scandinavian journal of clinical and laboratory investigation The association between ferritin and transferrin saturation (TS), respectively, and all-cause mortality is unclear. Furthermore, the influence of concurrent inflammation has not been sufficiently elucidated. We investigated these associations and the effect of concurrently elevated C-reactive protein (CRP), and accordingly report the levels associated with lowest all-cause mortality for females and males with and without inflammation.Blood test results from 161,921 individuals were included. Statistical analyses were performed in sex-stratified subpopulations, with ferritin or TS level as continuous exposure variables, and were adjusted for age, co-morbidity and inflammation status using CRP. An interaction was used to investigate whether the effect of ferritin or TS on all-cause mortality was modified by inflammation status (CRP ≥ 10 mg/L or CRP < 10 mg/L). Low and high ferritin and TS levels were respectively associated with increased all-cause mortality in females and in males. These associations persisted with concurrent CRP ≥ 10 mg/L. The ferritin level associated with lowest mortality was 60 µg/L for females and 125 µg/L for males with CRP < 10 mg/L. It was 52 µg/L for females and 118 µg/L for males with CRP ≥ 10 mg/L. The TS level associated with lowest mortality was 33.9% for females and 32.3% for males with CRP < 10 mg/L. It was 28.7% for females and 30.6% for males with CRP ≥ 10 mg/L.Our findings can nuance clinical interpretation and further aid in defining recommended ranges for ferritin and TS. 10.1080/00365513.2022.2129435
Iron deficiency screening is a key issue in chronic inflammatory diseases: A call to action. Journal of internal medicine Iron deficiency is frequent in patients with chronic inflammatory conditions (e.g., chronic heart failure, chronic kidney disease, cancers, and bowel inflammatory diseases). Indeed, high concentrations of inflammatory cytokines increase hepcidin concentrations that lead to the sequestration of iron in cells of the reticuloendothelial system (functional iron deficiency). Iron parameters are often assessed only in the context of anemia, but iron deficiency, even without anemia, is present in about half of patients with inflammatory conditions. Iron deficiency worsens underlying chronic diseases and is an independent factor of morbidity and mortality. In daily practice, the most effective biomarkers of iron status are serum ferritin, which reflects iron storage, and transferrin saturation, which reflects the transport of iron. Serum ferritin is increased in an inflammatory context, and there is still no consensus on the threshold to be used in chronic inflammatory conditions. Nevertheless, recent recommendations of international guidelines agreed to define iron deficiency by serum ferritin &lt;100 µg/L and/or transferrin saturation &lt;20%. Iron parameters remain, however, insufficiently assessed in patients with chronic inflammatory conditions. Indeed, clinical symptoms of iron deficiency, such as fatigue, are not specific and often confused with those of the primary disease. Iron repletion, preferably by the intravenous route to bypass tissue sequestration, improves clinical signs and quality of life. Because of the negative impact of iron deficiency on chronic inflammatory diseases and the efficacy of intravenous iron repletion, screening of iron parameters should be part of the routine examination of all patients with chronic inflammatory diseases. 10.1111/joim.13503
Prognostic Values of Serum Ferritin and D-Dimer Trajectory in Patients with COVID-19. Qeadan Fares,Tingey Benjamin,Gu Lily Y,Packard Ashley Hafen,Erdei Esther,Saeed Ali I Viruses Cytokine storm syndrome in patients with COVID-19 is mediated by pro-inflammatory cytokines resulting in acute lung injury and multiorgan failure. Elevation in serum ferritin and D-dimer is observed in COVID-19 patients. To determine prognostic values of optimal serum cutoff with trajectory plots for both serum ferritin and D-dimer in COVID-19 patients with invasive ventilator dependence and in-hospital mortality. We used retrospective longitudinal data from the Cerner COVID-19 de-identified cohort. COVID-19 infected patients with valid repeated values of serum ferritin and D-dimer during hospitalization were used in mixed-effects logistic-regression models. Among 52,411 patients, 28.5% (14,958) had valid serum ferritin and 28.6% (15,005) D-dimer laboratory results. Optimal cutoffs of ferritin (714 ng/mL) and D-dimer (2.1 mg/L) revealed AUCs ≥ 0.99 for in-hospital mortality. Optimal cutoffs for ferritin (502 ng/mL) and D-dimer (2.0 mg/L) revealed AUCs ≥ 0.99 for invasive ventilator dependence. Optimal cutoffs for in-house mortality, among females, were lower in serum ferritin (433 ng/mL) and D-dimer (1.9 mg/L) compared to males (740 ng/mL and 2.5 mg/L, respectively). Optimal cutoffs for invasive ventilator dependence, among females, were lower in ferritin (270 ng/mL) and D-dimer (1.3 mg/L) compared to males (860 ng/mL and 2.3 mg/L, respectively). Optimal prognostic cutoffs for serum ferritin and D-dimer require considering the entire trajectory of laboratory values during the disease course. Females have an overall lower optimal cutoff for both serum ferritin and D-dimer. The presented research allows health professionals to predict clinical outcomes and appropriate allocation of resources during the COVID-19 pandemic, especially early recognition of COVID-19 patients needing higher levels of care. 10.3390/v13030419
Optimal serum ferritin level range: iron status measure and inflammatory biomarker. DePalma Ralph G,Hayes Virginia W,O'Leary Timothy J Metallomics : integrated biometal science 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. 10.1093/mtomcs/mfab030
Anemia and iron metabolism in COVID-19: a systematic review and meta-analysis. Taneri Petek Eylul,Gómez-Ochoa Sergio Alejandro,Llanaj Erand,Raguindin Peter Francis,Rojas Lyda Z,Roa-Díaz Zayne Milena,Salvador Dante,Groothof Dion,Minder Beatrice,Kopp-Heim Doris,Hautz Wolf E,Eisenga Michele F,Franco Oscar H,Glisic Marija,Muka Taulant European journal of epidemiology 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 × 10 /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. 10.1007/s10654-020-00678-5
C-reactive protein, procalcitonin, D-dimer, and ferritin in severe coronavirus disease-2019: a meta-analysis. Therapeutic advances in respiratory disease BACKGROUND:Patients critically ill with coronavirus disease-2019 (COVID-19) feature hyperinflammation, and the associated biomarkers may be beneficial for risk stratification. We aimed to investigate the association between several biomarkers, including serum C-reactive protein (CRP), procalcitonin (PCT), D-dimer, and serum ferritin, and COVID-19 severity. METHODS:We performed a comprehensive systematic literature search through electronic databases. The outcome of interest for this study was the composite poor outcome, which comprises mortality, acute respiratory distress syndrome, need for care in an intensive care unit, and severe COVID-19. RESULTS:A total of 5350 patients were pooled from 25 studies. Elevated CRP was associated with an increased composite poor outcome [risk ratio (RR) 1.84 (1.45, 2.33),  < 0.001; I: 96%] and its severe COVID-19 (RR 1.41; I: 93%) subgroup. A CRP ⩾10 mg/L has a 51% sensitivity, 88% specificity, likelihood ratio (LR) + of 4.1, LR- of 0.5, and an area under curve (AUC) of 0.84. An elevated PCT was associated with an increased composite poor outcome [RR 3.92 (2.42, 6.35),  < 0.001; I: 85%] and its mortality (RR 6.26; I: 96%) and severe COVID-19 (RR 3.93; I: 63%) subgroups. A PCT ⩾0.5 ng/ml has an 88% sensitivity, 68% specificity, LR+ of 2.7, LR- of 0.2, and an AUC of 0.88. An elevated D-dimer was associated with an increased composite poor outcome [RR 2.93 (2.14, 4.01),  < 0.001; I: 77%], including its mortality (RR 4.15; I: 83%) and severe COVID-19 (RR 2.42; I: 58%) subgroups. A D-dimer >0.5 mg/L has a 58% sensitivity, 69% specificity, LR+ of 1.8, LR- of 0.6, and an AUC of 0.69. Patients with a composite poor outcome had a higher serum ferritin with a standardized mean difference of 0.90 (0.64, 1.15),  < 0.0001; I: 76%. CONCLUSION:This meta-analysis showed that an elevated serum CRP, PCT, D-dimer, and ferritin were associated with a poor outcome in COVID-19. 10.1177/1753466620937175
Ferritin in the coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis. Journal of clinical laboratory analysis OBJECTIVE:The coronavirus disease 2019 (COVID-19) has rapidly developed into a pandemic. Increased levels of ferritin due to cytokine storm and secondary hemophagocytic lymphohistiocytosis were found in severe COVID-19 patients. Therefore, the aim of this study was to determine the role of ferritin in COVID-19. METHODS:Studies investigating ferritin in COVID-19 were collected from PubMed, EMBASE, CNKI, SinoMed, and WANFANG. A meta-analysis was performed to compare the ferritin level between different patient groups: non-survivors versus survivors; more severe versus less severe; with comorbidity versus without comorbidity; ICU versus non-ICU; with mechanical ventilation versus without mechanical ventilation. RESULTS:A total of 52 records involving 10 614 COVID-19-confirmed patients between December 25, 2019, and June 1, 2020, were included in this meta-analysis, and 18 studies were included in the qualitative synthesis. The ferritin level was significantly increased in severe patients compared with the level in non-severe patients [WMD 397.77 (95% CI 306.51-489.02), P < .001]. Non-survivors had a significantly higher ferritin level compared with the one in survivors [WMD 677.17 (95% CI 391.01-963.33), P < .001]. Patients with one or more comorbidities including diabetes, thrombotic complication, and cancer had significantly higher levels of ferritin than those without (P < .01). Severe acute liver injury was significantly associated with high levels of ferritin, and its level was associated with intensive supportive care, including ICU transfer and mechanical ventilation. CONCLUSIONS:Ferritin was associated with poor prognosis and could predict the worsening of COVID-19 patients. 10.1002/jcla.23618
Lactoferrin: from the structure to the functional orchestration of iron homeostasis. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine Iron is by far the most widespread and essential transition metal, possessing crucial biological functions for living systems. Despite chemical advantages, iron biology has forced organisms to face with some issues: ferric iron insolubility and ferrous-driven formation of toxic radicals. For these reasons, acquisition and transport of iron constitutes a formidable challenge for cells and organisms, which need to maintain adequate iron concentrations within a narrow range, allowing biological processes without triggering toxic effects. Higher organisms have evolved extracellular carrier proteins to acquire, transport and manage iron. In recent years, a renewed interest in iron biology has highlighted the role of iron-proteins dysregulation in the onset and/or exacerbation of different pathological conditions. However, to date, no resolutive therapy for iron disorders has been found. In this review, we outline the efficacy of Lactoferrin, a member of the transferrin family mainly secreted by exocrine glands and neutrophils, as a new emerging orchestrator of iron metabolism and homeostasis, able to counteract iron disorders associated to different pathologies, including iron deficiency and anemia of inflammation in blood, Parkinson and Alzheimer diseases in the brain and cystic fibrosis in the lung. 10.1007/s10534-022-00453-x
The role of iron homeostasis in remodeling immune function and regulating inflammatory disease. Science bulletin The essential trace element iron regulates a wide range of biological processes in virtually all living organisms. Because both iron deficiency and iron overload can lead to various pathological conditions, iron homeostasis is tightly regulated, and understanding this complex process will help pave the way to developing new therapeutic strategies for inflammatory disease. In recent years, significant progress has been made with respect to elucidating the roles of iron and iron-related genes in the development and maintenance of the immune system. Here, we review the timing and mechanisms by which systemic and cellular iron metabolism are regulated during the inflammatory response and during infectious disease, processes in which both the host and the pathogen compete for iron. We also discuss the evidence and implications that immune cells such as macrophages, T cells, and B cells require sufficient amounts of iron for their proliferation and for mediating their effector functions, in which iron serves as a co-factor in toll-like receptor 4 (TLR4) signaling, mitochondrial respiration, posttranslational regulation, and epigenetic modification. In addition, we discuss the therapeutic implications of targeting ferroptosis, iron homeostasis and/or iron metabolism with respect to conferring protection against pathogen infection, controlling inflammation, and improving the efficacy of immunotherapy. 10.1016/j.scib.2021.02.010
Ferritin: An Inflammatory Player Keeping Iron at the Core of Pathogen-Host Interactions. Moreira Ana C,Mesquita Gonçalo,Gomes Maria Salomé Microorganisms Iron is an essential element for virtually all cell types due to its role in energy metabolism, nucleic acid synthesis and cell proliferation. Nevertheless, if free, iron induces cellular and organ damage through the formation of free radicals. Thus, iron levels must be firmly controlled. During infection, both host and microbe need to access iron and avoid its toxicity. Alterations in serum and cellular iron have been reported as important markers of pathology. In this regard, ferritin, first discovered as an iron storage protein, has emerged as a biomarker not only in iron-related disorders but also in inflammatory diseases, or diseases in which inflammation has a central role such as cancer, neurodegeneration or infection. The basic research on ferritin identification and functions, as well as its role in diseases with an inflammatory component and its potential as a target in host-directed therapies, are the main considerations of this review. 10.3390/microorganisms8040589
Expanding the spectrum of the hyperferritinemic syndrome, from pathogenic mechanisms to clinical observations, and therapeutic implications. Autoimmunity reviews From the introduction of hyperferritinemic syndrome concept, a growing body of evidence has suggested the role of ferritin as a pathogenic mediator and a relevant clinical feature in the management of patients with inflammatory diseases. From a pathogenic point of view, ferritin may directly stimulate the aberrant immune response by triggering the production of pro-inflammatory mediators in inducing a vicious pathogenic loop and contributing to the occurrence of cytokine storm syndrome. The latter has been recently defined as a clinical picture characterised by elevated circulating cytokine levels, acute systemic inflammatory symptoms, and secondary organ dysfunction beyond that which could be attributed to a normal response to a pathogen It is noteworthy that the occurrence of hyperferritinemia may be correlated with the development of the cytokine storm syndrome in the context of an inflammatory disease. In addition to adult onset Still's disease, macrophage activation syndrome, catastrophic anti-phospholipids syndrome, and septic shock, recent evidence has suggested this association between ferritin and life-threatening evolution in patients with systemic lupus erythematosus, with anti-MDA5 antibodies in the context of poly-dermatomyositis, with severe COVID-19, and with multisystem inflammatory syndrome. The possible underlying common inflammatory mechanisms, associated with hyperferritinemia, may led to the similar clinical picture observed in these patients. Furthermore, similar therapeutic strategies could be suggested inhibiting pro-inflammatory cytokines and improving long-term outcomes in these disorders. Thus, it could be possible to expand the spectrum of the hyperferritinemic syndrome to those diseases burdened by a dreadful clinical picture correlated with hyperferritinemia and the occurrence of the cytokine storm syndrome. In addition, the assessment of ferritin may provide useful information to the physicians in clinical practice to manage these patients. Therefore, ferritin may be considered a relevant clinical feature to be used as biomarker in dissecting the unmet needs in the management of these disorders. Novel evidence may thus support an expansion of the spectrum of the hyperferritinemic syndrome to these diseases burdened by a life-threatening clinical picture correlated with hyperferritinemia and the occurrence of the cytokine storm syndrome. 10.1016/j.autrev.2022.103114
Hereditary Hyperferritinemia. International journal of molecular sciences Ferritin is a ubiquitous protein that is present in most tissues as a cytosolic protein. The major and common role of ferritin is to bind Fe, oxidize it and sequester it in a safe form in the cell, and to release iron according to cellular needs. Ferritin is also present at a considerably low proportion in normal mammalian sera and is relatively iron poor compared to tissues. Serum ferritin might provide a useful and convenient method of assessing the status of iron storage, and its measurement has become a routine laboratory test. However, many additional factors, including inflammation, infection, metabolic abnormalities, and malignancy-all of which may elevate serum ferritin-complicate interpretation of this value. Despite this long history of clinical use, fundamental aspects of the biology of serum ferritin are still unclear. According to the high number of factors involved in regulation of ferritin synthesis, secretion, and uptake, and in its central role in iron metabolism, hyperferritinemia is a relatively common finding in clinical practice and is found in a large spectrum of conditions, both genetic and acquired, associated or not with iron overload. The diagnostic strategy to reveal the cause of hyperferritinemia includes family and personal medical history, biochemical and genetic tests, and evaluation of liver iron by direct or indirect methods. This review is focused on the forms of inherited hyperferritinemia with or without iron overload presenting with normal transferrin saturation, as well as a step-by-step approach to distinguish these forms to the acquired forms, common and rare, of isolated hyperferritinemia. 10.3390/ijms24032560
Ferritin - from iron, through inflammation and autoimmunity, to COVID-19. Journal of autoimmunity While it took decades to arrive to a conclusion that ferritin is more than an indicator of iron storage level, it took a short period of time through the COVID-19 pandemic to wonder what the reason behind high levels of ferritin in patients with severe COVID-19 might be. Unsurprisingly, acute phase reactant was not a satisfactory explanation. Moreover, the behavior of ferritin in patients with severe COVID-19 and the subsequent high mortality rates in patients with high ferritin levels necessitated further investigations to understand the role of ferritin in the diseases. Ferritin was initially described to accompany various acute infections, both viral and bacterial, indicating an acute response to inflammation. However, with the introduction of the hyperferritinemic syndrome connecting four severe pathological conditions such as adult-onset Still's disease, macrophage activation syndrome, catastrophic antiphospholipid syndrome, and septic shock added another aspect of ferritin where it could have a pathogenetic role rather than an extremely elevated protein only. In fact, suggesting that COVID-19 is a new member in the spectrum of hyperferritinemic syndrome besides the four mentioned conditions could hopefully direct further search on the pathogenetic role of ferritin. Doubtlessly, improving our understanding of those aspects of ferritin would enormously contribute to better coping with severe diseases in terms of treatment and prevention of complications. The origin, history, importance, and the advances of searching the role of ferritin in various pathological and clinical processes are presented hereby in our article. In addition, the implications of ferritin in COVID-19 are addressed. 10.1016/j.jaut.2021.102778
Severe Yellow Fever and Extreme Hyperferritinemia Managed with Therapeutic Plasma Exchange. Sztajnbok Jaques,Sant'Ana Malaque Ceila Maria,Nihei Camila Hitomi,Duayer Irene Faria,Leme Britto Zita Maria,Beraldo Eduarda Gambini,AzevedoTeixeira Ralcyon Francis The American journal of tropical medicine and hygiene A 43-year-old man was admitted to the intensive care unit and diagnosed with yellow fever. He presented with refractory bleeding, extreme hyperferritinemia, and multiple organ dysfunction syndrome, requiring renal replacement therapy, mechanical ventilation, and treatment with vasoactive drugs. Because the bleeding did not respond to fresh-frozen plasma administration, the patient received therapeutic plasma exchange, which was accompanied by a marked improvement of the clinical and biochemical parameters, including a significant decline in serum ferritin levels. 10.4269/ajtmh.19-0219
Reference intervals of acute phase proteins in healthy Andalusian donkeys and response to experimentally induced endotoxemia. Journal of veterinary internal medicine BACKGROUND:Assessment of acute phase proteins (APPs) may allow prompt detection of diseases in donkeys, that otherwise may be missed because of the stoic behavior of donkeys. Reference intervals (RIs) of APPs measured using immunoassays and a comparison of the response of these biomarkers to a controlled inflammatory insult are lacking in donkeys. OBJECTIVES:(a) To describe the RIs for APPs in healthy Andalusian donkeys, (b) to study the effects of sex and age on APPs, and (c) to assess the early response of APPs to experimentally induced endotoxemia. ANIMALS:Seventy-three healthy Andalusian donkeys (67 for RIs and 6 for endotoxemia). METHODS:Serum amyloid A (SAA), haptoglobin (Hp), C-reactive protein (CRP), ceruloplasmin (Cp), α1-acid glycoprotein (AGP), procalcitonin (PCT), ferritin (Ft), and fibrinogen (Fb) RIs were determined. Endotoxemia was induced and samples for APP determination were obtained at regular intervals for 4 hours. RESULTS:The RIs in Andalusian donkeys were: SAA (0.1-0.6 mg/L), Hp (75-2261 mg/L), CRP (1.3-7.0 mg/L), Cp (0-745 mg/L), AGP (0-884 mg/L), PCT (0-504 pg/mL), Ft (26.9-31.8 μg/L), and Fb (115-466 mg/dL). Concentrations of SAA were higher (P < .05) in jacks. Donkeys <5 years old had higher Cp, AGP, and PCT compared to older donkeys. Concentrations of SAA and Hp were significantly increased in endotoxemic donkeys from 2 hours postinduction. CONCLUSIONS AND CLINICAL IMPORTANCE:We illustrated the importance of using species-specific RIs for APPs in donkeys and the effect of age and sex on APP concentrations. Concentrations of SAA and Hp appear to be the most useful biomarkers in donkeys in the early stages of endotoxemia. 10.1111/jvim.16015
Mortality and clinical characteristics of multisystem inflammatory syndrome in children (MIS-C) associated with covid-19 in critically ill patients: an observational multicenter study (MISCO study). BMC pediatrics BACKGROUND:The clinical presentation and severity of Multisystem Inflammatory Syndrome in Children associated with COVID-19 (MIS-C) is widespread and presents a very low mortality rate in high-income countries. This research describes the clinical characteristics of MIS-C in critically ill children in middle-income countries and the factors associated with the rate of mortality and patients with critical outcomes. METHODS:An observational cohort study was conducted in 14 pediatric intensive care units (PICUs) in Colombia between April 01, 2020, and January 31, 2021. Patient age ranged between one month and 18 years, and each patient met the requirements set forth by the World Health Organization (WHO) for MIS-C. RESULTS:There were seventy-eight children in this study. The median age was seven years (IQR 1-11), 18 % (14/78) were under one year old, and 56 % were male. 35 % of patients (29/78) were obese or overweight. The PICU stay per individual was six days (IQR 4-7), and 100 % had a fever upon arrival to the clinic lasting at least five days (IQR 3.7-6). 70 % (55/78) of patients had diarrhea, and 87 % (68/78) had shock or systolic myocardial dysfunction (78 %). Coronary aneurysms were found in 35 % (27/78) of cases, and pericardial effusion was found in 36 %. When compared to existing data in high-income countries, there was a higher mortality rate observed (9 % vs. 1.8 %; p=0.001). When assessing the group of patients that did not survive, a higher frequency of ferritin levels was found, above 500 ngr/mL (100 % vs. 45 %; p=0.012), as well as more cardiovascular complications (100 % vs. 54 %; p = 0.019) when compared to the group that survived. The main treatments received were immunoglobulin (91 %), vasoactive support (76 %), steroids (70.5 %) and antiplatelets (44 %). CONCLUSIONS:Multisystem Inflammatory Syndrome in Children due to SARS-CoV-2 in critically ill children living in a middle-income country has some clinical, laboratory, and echocardiographic characteristics similar to those described in high-income countries. The observed inflammatory response and cardiovascular involvement were conditions that, added to the later presentation, may explain the higher mortality seen in these children. 10.1186/s12887-021-02974-9
Comparison of Characteristics and Outcomes of Multisystem Inflammatory Syndrome, Kawasaki Disease and Toxic Shock Syndrome in Children. Medicina (Kaunas, Lithuania) Since the first cases of multisystem inflammatory syndrome in children (MIS-C) in April 2020, the diagnostic challenge has been to recognize this syndrome and to differentiate it from other clinically similar pathologies such as Kawasaki disease (KD) and toxic shock syndrome (TSS). Our objective is to compare clinical signs, laboratory data and instrumental investigations between patients with MIS-C, KD and TSS. This retrospective observational study was conducted at the Children's Clinical University Hospital, Latvia (CCUH). We collected data from all pediatric patients <18 years of age, who met the Centers for Disease Control and Prevention case definition for MIS-C, and who presented to CCUH between December 2020 and December 2021. We also retrospectively reviewed data from inpatient medical records of patients <18 years of age diagnosed as having KD and TSS at CCUH between December 2015 and December 2021. : In total, 81 patients were included in this study: 39 (48.1%) with KD, 29 (35.8%) with MIS-C and 13 (16.1%) with TSS. In comparison with TSS and KD, patients with MIS-C more often presented with gastrointestinal symptoms (abdominal pain ( < 0.001), diarrhea ( = 0.003)), shortness of breath ( < 0.02) and headache ( < 0.003). All MIS-C patients had cardiovascular involvement and 93.1% of MIS-C patients fulfilled KD criteria, showing higher prevalence than in other research. Patients with KD had higher prevalence of cervical lymphadenopathy ( < 0.006) and arthralgias ( < 0.001). In comparison with KD and TSS, MIS-C patients had higher levels of ferritin ( < 0.001), fibrinogen ( = 0.04) and cardiac biomarkers, but lower levels of platelets and lymphocytes ( < 0.001). KD patients tended to have lower peak C-reactive protein (CRP) ( < 0.001), but higher levels of platelets. Acute kidney injury was more often observed in TSS patients ( = 0.01). Pathological changes in electrocardiography (ECG) and echocardiography were significantly more often observed in MIS-C patients ( < 0.001). This research shows that MIS-C, KD and TSS have several clinical similarities and additional investigations are required for reaching final diagnosis. All the patients with suspected MIS-C diagnosis should be examined for possible cardiovascular involvement including cardiac biomarkers, ECG and echocardiography. 10.3390/medicina59030626
Clinical manifestations, complications, and outcomes of patients with COVID-19 in Sudan: a multicenter observational study. Tropical medicine and health BACKGROUND:Coronavirus disease 2019 (COVID-19) is a pandemic caused by a newly discovered coronavirus. Although clinical manifestations of COVID-19 are mainly pulmonary, some patients have other systemic manifestations. This study aimed to describe the clinical finding and outcomes in Sudanese patients diagnosed with COVID-19. METHODS:This retrospective observational study is based on documented files that included patients diagnosed with COVID-19 in seven selected hospitals inside Khartoum. Clinical manifestations, complications and outcomes were extracted from patients' records using an extraction form designed for this study. RESULTS:Data of 243 patients diagnosed with COVID-19 were analyzed. The mean (SD) age in years was 55.8 (18.4). Out of 116 participants, 27 of them (23.3%) had severe disease, 15 (12.9%) were critically ill. 67.5% of patients were admitted to the hospital within 7 days from onset of symptoms; most of them were admitted to the wards (n = 140,72.5%). Fever (83.2%), cough (70.7%), and shortness of breath (69.2%) were the most commonly recorded clinical manifestations. Sepsis (9.8%) and acidosis (7.8%) were the most frequently reported complications. Death was the final outcome in 21.4% (56/243). Older age and presence of diabetes were found significantly associated with in-hospital death. The laboratory results showed high CRP in 85.6% (119/139), high ferritin in 88.9% (24/27), lactate dehydrogenase had a median of 409.0 (359-760), D-dimer had a median of 3.3 (1.2-16. 6), and 53/105 (50.5%) had low albumin. CONCLUSIONS:Fever was the most mentioned sign among the participants, followed by fatigue. Cough and shortness of breath were the most commonly recorded pulmonary symptoms manifested. Our study showed multiple variables were associated with in-hospital death. The mortality rate was high among severe and critically ill patients diagnosed with COVID-19. 10.1186/s41182-021-00382-4
Suspecting Haemophagocytic Lymphohistiocytosis (Hlh) In Patients With A High Ferritin. Journal of Ayub Medical College, Abbottabad : JAMC Heamophagocytic Lymphohistiocytosis (HLH) is problematic to diagnose. The conditions that predispose to HLH present in a similar fashion, such as sepsis and haematological cancers. We look at the case of a 66-year-old man with a diagnosis of CLL, who presented with pyrexia and non-specific symptoms which included abdominal discomfort and weight loss. Sepsis, the principal suspicion was thoroughly investigated and excluded. Routine autoimmune pathologies were exhausted with comprehensive panels. The patient was trialled on steroids, presumptively, with a limited response. What was most peculiar in his blood tests was an unusually high Ferritin of > 50000. The parent clinical team was at a loss to explain the unusually high ferritin when a locum consultant suggested the diagnosis of Haemophagocytic Lymphohistiocytosis based on a similar presentation she had observed many years ago. The patient was started on pulsed Etoposide and Dexamethasone, however, unfortunately, he could not make a recovery. 10.55519/JAMC-01-10262
Association of Hyperferritinemia With Distinct Host Response Aberrations in Patients With Community-Acquired Pneumonia. The Journal of infectious diseases BACKGROUND:Strongly elevated ferritin levels have been proposed to reflect systemic hyperinflammation in patients admitted to the intensive care unit. Knowledge of the incidence and pathophysiological implications of hyperferritinemia in patients with acute infection admitted to a non-intensive care setting is limited. METHODS:We determined the association between hyperferritinemia, defined by 2 cutoff values (500 and 250 ng/mL), and aberrations in key host response mechanisms among patients with community-acquired pneumonia (CAP) on admission to a general hospital ward (clinicaltrials.gov NCT02928367; trialregister.nl NTR6163). RESULTS:Plasma ferritin levels were higher in patients with CAP (n = 174; median [interquartile ranges], 259.5 [123.1-518.3] ng/mL) than in age- and sex-matched controls without infection (n = 50; 102.8 [53.5-185.7] ng/mL); P < .001); they were ≥500 ng/mL in 46 patients (26%) and ≥250 ng/mL in 90 (52%). Measurements of 26 biomarkers reflective of distinct pathophysiological domains showed that hyperferritinemia was associated with enhanced systemic inflammation, neutrophil activation, cytokine release, endothelial cell activation and dysfunction, and activation of the coagulation system. Results were robust across different cutoff values. CONCLUSIONS:Hyperferritinemia identifies patients with CAP with a broad deregulation of various host response mechanisms implicated in the pathogenesis of sepsis. This could inform future therapeutic strategies targeting subgroups within the CAP population. 10.1093/infdis/jiac013
The evolving value of older biomarkers in the clinical diagnosis of pediatric sepsis. Pediatric research Sepsis remains the leading cause of childhood mortality worldwide. The evolving definition of pediatric sepsis is extrapolated from adult studies. Although lacking formal validation in the pediatric population, this working definition has historically proven its clinical utility. Prompt identification of pediatric sepsis is challenging as clinical picture is often variable. Timely intervention is crucial for optimal outcome, thus biomarkers are utilized to aid in immediate, yet judicious, diagnosis of sepsis. Over time, their use in sepsis has expanded with discovery of newer biomarkers that include genomic bio-signatures. Despite recent scientific advances, there is no biomarker that can accurately diagnose sepsis. Furthermore, older biomarkers are readily available in most institutions while newer biomarkers are not. Hence, the latter's clinical value in pediatric sepsis remains theoretical. Albeit promising, scarce data on newer biomarkers have been extracted from research settings making their clinical value unclear. As interest in newer biomarkers continue to proliferate despite their ambiguous clinical use, the literature on older biomarkers in clinical settings continue to diminish. Thus, revisiting the evolving value of these earliest biomarkers in optimizing pediatric sepsis diagnosis is warranted. This review focuses on the four most readily available biomarkers to bedside clinicians in diagnosing pediatric sepsis. IMPACT: The definition of pediatric sepsis remains an extrapolation from adult studies. Older biomarkers that include C-reactive protein, procalcitonin, ferritin, and lactate are the most readily available biomarkers in most pediatric institutions to aid in the diagnosis of pediatric sepsis. Older biomarkers, although in varying levels of reliability, remain to be useful clinical adjuncts in the diagnosis of pediatric sepsis if used in the appropriate clinical context. C-reactive protein and procalcitonin are more sensitive and specific among these older biomarkers in diagnosing pediatric sepsis although evidence varies in different age groups and clinical scenarios. 10.1038/s41390-022-02190-w
Procalcitonin and High APACHE (Acute Physiological and Chronic Health Evaluation) Level Are Associated with the Course of Acute Kidney Injury in Patients with SARS-CoV-2. International journal of clinical practice Background:Acute kidney injury (AKI) is associated with poor outcomes in patients infected with SARS-CoV-2. Sepsis, direct injury to kidney cells by the virus, and severe systemic inflammation are mechanisms implicated in its development. We investigated the association between inflammatory markers (C-reactive protein, procalcitonin, D-dimer, lactate dehydrogenase, and ferritin) in patients infected with SARS-CoV-2 and the development of AKI. Methods:A prospective cohort study performed at the Civil Hospital (Dr. Juan I. Menchaca) Guadalajara, Mexico, included patients aged >18 years with a diagnosis of SARS-CoV-2 pneumonia confirmed by RT-PCR and who did or did not present with AKI (KDIGO) while hospitalized. Biomarkers of inflammation were recorded, and kidney function was estimated using the CKD-EPI formula. Results:291 patients were included (68% males; average age, 57 years). The incidence of AKI was 40.5% (118 patients); 21% developed stage 1 AKI, 6% developed stage 2 AKI, and 14% developed stage 3 AKI. The development of AKI was associated with higher phosphate ( = 0.002) (RR 1.39, CI 95% 1.13-1.72), high procalcitonin levels at hospital admission ( = 0.005) (RR 2.09, CI 95% 1.26-3.50), and high APACHE scores ( = 0.011) (RR 2.0, CI 95% 1.17-3.40). The survival analysis free of AKI according to procalcitonin levels and APACHE scores demonstrated a lower survival in patients with procalcitonin >0.5 ng/ml ( = 0.001) and APACHE >15 points ( = 0.004). Conclusions:Phosphate, high procalcitonin levels, and APACHE levels >15 were predictors of AKI development in patients hospitalized with COVID-19. 10.1155/2022/1363994
Comparison of Standard and New Iron Status Biomarkers: A Prospective Cohort Study in Sepsis Patients. Healthcare (Basel, Switzerland) Both iron deficiency (ID) and iron overload can have negative effects on the risk and course of infection. Therefore, the ability to accurately assess iron status in these patients is of the utmost importance. Systemic inflammation in sepsis patients affects the results of standard iron biomarkers and makes accurate diagnosis of ID problematic. The aim of our study was to analyze the association between widely available standard iron biomarkers and selected new iron biomarkers in various iron status subgroups among sepsis patients. Consecutive patients diagnosed with sepsis or septic shock and procalcitonin concentration > 0.5 ng/mL were enrolled. The following iron biomarkers were determined: iron, ferritin, transferrin, transferrin saturation, reticulocyte (Ret) number and percentage, Ret hemoglobin equivalent, Ret fluorescence subpopulations, and hepcidin concentration. The study group comprised 90 study subjects. There were 42 (47%) patients with normal iron status, 6 (6%) with ID without anemia, and 42 (47%) with ID anemia. No meaningful correlation exists between standard and new iron biomarkers in various iron status subgroups among sepsis patients. Therefore, standard iron biomarkers cannot be used to diagnose ID in this cohort. 10.3390/healthcare11070995
Prediction of Poor Outcomes for Septic Children According to Ferritin Levels in a Middle-Income Setting. Tonial Cristian T,Costa Caroline A D,Andrades Gabriela R H,Crestani Francielly,Einloft Paulo R,Bruno Francisco,Miranda Ana P,Fiori Humberto H,Garcia Pedro Celiny R Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies OBJECTIVES:To evaluate serum ferritin measured within 48 hours of admission as a prognostic marker and examine the association with unfavorable outcomes in a population of pediatric patients with sepsis and high prevalence of iron deficiency anemia in which this biomarker is routinely measured. DESIGN:Retrospective cohort study. SETTING:PICU of a tertiary care teaching hospital in a middle-income country in South America. PATIENTS:All patients 6 months to 18 years old (n = 350) admitted with a diagnosis of sepsis, suspected or proven, were eligible for inclusion. Exclusion criteria were length of PICU stay less than 8 hours and inherited or acquired disorder of iron metabolism that could interfere with serum ferritin levels. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Three-hundred twelve patients had their ferritin levels measured within 48 hours, and only 38 did not. The prevalence of iron deficiency anemia (hemoglobin < 11 g/dL and mean corpuscular volume < 80 fl was 40.3%. The median of the highest serum ferritin level within 48 hours was 150.5 ng/mL (interquartile range, 82.25-362 ng/mL), being associated with mortality (p < 0.001; Exp(B), 5.170; 95% CI, 2.619-10.205). A 10-fold increase in ferritin level was associated with a five-fold increase in mortality. There was a monotonic increase in mortality with increasing ferritin levels (p < 0.05). Regarding the discriminatory power of ferritin for mortality, the area under the receiver operating characteristic curve was 0.787 (95% CI, 0.737-0.83; p < 0.0001). CONCLUSIONS:Serum ferritin at lower thresholds predicts mortality in children with sepsis admitted to the ICU in a middle-income country with high prevalence of iron deficiency anemia. 10.1097/PCC.0000000000002273
Analysis of the occurrence of hemophagocytic lymphohistiocytosis (HLH) features in patients with sepsis: a prospective study. Bursa Dominik,Bednarska Agnieszka,Pihowicz Andrzej,Paciorek Marcin,Horban Andrzej Scientific reports HLH syndrome may mimic sepsis but requires entirely different treatment. The aim of the study was to assess the occurrence of HLH features in patients with sepsis and the influence these exert on the patients' prognosis. The prospective study included 108 patients with suspected sepsis who were routinely evaluated according to HLH criteria. They were divided into group I (SOFA = 2, n = 57) and group II (SOFA ≥ 3, n = 51). Four patients were excluded from analysis: 1 with real HLH, 2 with Still's disease and 1 with lymphoma. The median (IQR) concentration of ferritin was 613.4 (850.3) ng/mL, however 6 patients revealed a remarkedly high ferritin concentration > 3000 ng/mL, including 2 with ferritin > 10,000 ng/mL. In total, 21 patients met ≥ 4/8 HLH criteria and were found to have sepsis with HLH-like syndrome (SHLS). Out of these, 19 responded to antimicrobials, 2 died due to infection. The sepsis patients presented with the following HLH criteria: fever (95.2%), hyperferritinemia (57.3%), splenomegaly (43.4%), reduced NK cell activity (35.2%), high sCD25 activity (27.4%) and rarely: hypertriglyceridemia (14.4%), duopenia (5.8%), hypofibrinogenemia (1.9%). Although group II patients had higher odds for SHLS presentation (OR 3.26, p = 0.026) and for death (OR 14.3, p = 0.013), SHLS occurrence had no impact on the risk of death (OR 0.77, p = 0.75). Sepsis patients can present with SHLS exclusively due to severe infection. Duopenia, hypertriglyceridemia, hypofibrinogenemia and high level of sCD25 are unusual in sepsis and might indicate real HLH syndrome. Hyperferritinemia, even as high as in real HLH syndrome, can occur in sepsis patients. 10.1038/s41598-021-90046-4
Reevaluating the role of ferritin in the diagnosis of adult secondary hemophagocytic lymphohistiocytosis. Naymagon Leonard,Tremblay Douglas,Mascarenhas John European journal of haematology BACKGROUND:The standard diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH) include hyperferritinemia to >500 ng/mL. This ferritin threshold is based on pediatric data, and evidence for its application among adults with secondary HLH is lacking. OBJECTIVE AND METHODS:We conducted a retrospective study assessing the relationship between extreme hyperferritinemia and adult secondary HLH at our institution. All adult inpatients seen over a 10-year period, with serum ferritin >5000 ng/mL, were included. RESULTS:Among 1055 patients with serum ferritin >5000 ng/mL, there were 69 cases of HLH (HLH prevalence of 6.5%). Mean ferritin among HLH patients was 70 398 ng/mL (SD 122 908), median 40 019 ng/mL (IQR 16 051-68 326). The prevalence of HLH only reached 50% as serum ferritin approached 90 000 ng/mL. A variety of conditions were contributory to hyperferritinemia, most commonly bacterial sepsis (33%), hematologic malignancy (29%), renal failure (24%), and liver injury (18%). The optimal cutoff ferritin for diagnosis of HLH was 16 000 ng/mL (sensitivity 79.4%, specificity 79.2%, PPV 20.9%, and NPV 98.2%). CONCLUSIONS:The threshold ferritin levels used in diagnostic criteria for adult secondary HLH are too low to be clinically relevant, and efforts should be undertaken to revise them upward. Similar reappraisals should be taken of the other criteria used to diagnose adult HLH. 10.1111/ejh.13391
Lysosomal iron recycling in mouse macrophages is dependent upon both LcytB and Steap3 reductases. Blood advances Iron that is stored in macrophages as ferritin can be made bioavailable by degrading ferritin in the lysosome and releasing iron back into the cytosol. Iron stored in ferritin is found as Fe3+ and must be reduced to Fe2+ before it can be exported from the lysosome. Here we report that the lysosomal reductase Cyb561a3 (LcytB) and the endosomal reductase six-transmembrane epithelial antigen of prostate 3 (Steap3) act as lysosomal ferrireductases in the mouse macrophage cell line RAW264.7 converting Fe3+ to Fe2+ for iron recycling. We determined that when lysosomes were loaded with horse cationic ferritin, reductions or loss of LcytB or Steap3 using CRISPR/Cas9-mediated knockout technology resulted in decreased lysosomal iron export. Loss of both reductases was additive in decreasing lysosomal iron export. Decreased reductase activity resulted in increased transcripts for iron acquisition proteins DMT1 and transferrin receptor 1 (Tfrc1) suggesting that cells were iron limited. We show that transcript expression of LcytB and Steap3 is decreased in macrophages exposed to Escherichia coli pathogen UTI89, which supports a role for these reductases in regulating iron availability for pathogens. We further show that loss of LcytB and Steap3 in macrophages infected with UTI89 led to increased proliferation of intracellular UTI89 suggesting that the endolysosomal system is retaining Fe3+ that can be used for proliferation of intravesicular pathogens. Together, our findings reveal an important role for both LcytB and Steap3 in macrophage iron recycling and suggest that limiting iron recycling by decreasing expression of endolysosomal reductases is an innate immune response to protect against pathogen proliferation and sepsis. 10.1182/bloodadvances.2021005609
Early immune system alterations in patients with septic shock. Frontiers in immunology This study aims to investigate the early changes in the immune systems of patients with septic shock. A total of 243 patients with septic shock were included in this study. The patients were classified as survivors (n = 101) or nonsurvivors (n = 142). Clinical laboratories perform tests of the immune system's function. Each indicator was studied alongside healthy controls (n = 20) of the same age and gender as the patients. A comparative analysis of every two groups was conducted. Univariate and multivariate logistic regression analyses were performed to identify mortality risk factors that are independent of one another. In septic shock patients, neutrophil counts, infection biomarkers (C-reactive protein, ferritin, and procalcitonin levels), and cytokines (IL-1β, IL-2R, IL-6, IL-8, IL-10, and TNF-α) increased significantly. Lymphocyte and their subset counts (T, CD4+ T, CD8+ T, B, and natural killer cell counts), lymphocyte subset functions (the proportions of PMA/ionomycin-stimulated IFN-γ positive cells in CD4+ T cells), immunoglobulin levels (IgA, IgG, and IgM), and complement protein levels (C3 and C4) decreased significantly. Compared to survivors, nonsurvivors had higher levels of cytokines (IL-6, IL-8, and IL-10) but lower levels of IgM, complement C3 and C4, and lymphocyte, CD4+, and CD8+ T cell counts. Low IgM or C3 concentrations and low lymphocyte or CD4+ T cell counts were independent risk factors for mortality. These alterations should be considered in the future development of immunotherapies aimed at treating septic shock. 10.3389/fimmu.2023.1126874
Prevalence and predictors of in-hospital mortality of patients hospitalized with COVID-19 infection. Journal of infection and public health BACKGROUND:The severity and mortality from COVID-19 infection vary among populations. The aim of this study was to determine the prevalence and predictors of mortality among patients hospitalized with COVID-19 infection in a tertiary care hospital in Oman. METHODS:We conducted a retrospective study using database that included: demographic, clinical characteristics, laboratory parameters, medications and clinical outcomes of all patients hospitalized in Royal Hospital, Muscat, Oman, between March 12, 2020 and December 1st 2020. Univariate and multivariate logistic regression was performed to investigate the relationship between each variable and the risk of death of COVID-19 infected patients. RESULTS:In total,1002 patients with COVID-19 infection with mean age of the cohort was 54±16 years (65% (n=650) male) were included, with an overall and intensive care unit (ICU) mortalities of 26% (n=257) and 42% (n=199/473), respectively. The prevalence of ICU admission was 47% (n=473) and the need for mechanical ventilation was 41% (n=413). The overall length of stay in the ICU was 13 (9-21) days. Adjusting for other factors in the model, the multivariable logistic regression demonstrated that in-hospital mortality in admitted COVID-19 patients was associated with old age (p<0.001), heart diseases (adjusted odds ratio (aOR), 1.84; 95% confidence interval (CI): 1.11-3.03; p=0.018), liver diseases (aOR, 4.48; 95% CI: 1.04-19.3; p=0.044), those with higher ferritin levels (aOR, 1.00; 95% CI: 1.00-1.00; p=0.006), acute respiratory distress syndrome (ARDS) (aOR, 3.20; 95% CI: 1.65-6.18; p=0.001), sepsis (aOR, 1.77; 95% CI: 1.12-2.80; p=0.022), and those that had ICU admission (aOR, 2.22; 95% CI: 1.12-4.38; p=0.022). CONCLUSION:In this cohort, mortality in hospitalized COVID-19 patients was high and was associated with advanced age, heart diseases, liver disease, high ferritin, ARDS, sepsis and ICU admission. These high-risk groups should be prioritized for COVID-19 vaccinations. 10.1016/j.jiph.2021.03.016
DNA Viremia Is Associated with Hyperferritinemia in Pediatric Sepsis. Simon Dennis W,Halstead E Scott,Davila Sam,Kernan Kate F,Clark Robert S B,Storch Gregory,Carcillo Joseph A The Journal of pediatrics OBJECTIVE:To evaluate the relationship between detection of DNA viruses, ferritin, and outcomes in children with severe sepsis. STUDY DESIGN:We enrolled 75 pediatric patients with severe sepsis admitted to a tertiary care children's hospital. Plasma ferritin was measured within 48 hours of diagnosis and subsequently twice weekly. Herpes simplex type 1, human herpesvirus 6, Epstein-Barr virus, cytomegalovirus, and adenovirus DNAemia were assessed by polymerase chain reaction. RESULTS:The incidence of DNAemia was increased significantly in patients with ferritin ≥1000 ng/mL (78% vs 28%; P < .05). Patients with ferritin ≥1000 ng/mL were more likely to have multiple DNA viruses detected in plasma (39% vs 4%; P < .001). The number of viruses detected in plasma directly correlated with the degree of hyperferritinemia and development of combined hepatobiliary and hematologic dysfunction after we controlled for bacterial and fungal coinfections (P < .05) as well as increased mortality after we controlled for severity of illness and cancer diagnosis (OR 2.6, 95% CI 1.1-6.3, P < .05). CONCLUSIONS:Viral DNAemia was associated with hyperferritinemia and adverse outcome in pediatric severe sepsis. Prospective studies are needed to determine whether hyperferritinemia may be used to identify patients at risk of occult DNAemia. 10.1016/j.jpeds.2019.06.033
BIOMARKERS: CAN THEY REALLY GUIDE OUR DAILY PRACTICE? Shock (Augusta, Ga.) ABSTRACT:Optimal management of septic patients requires accurate assessment of both current severity status and prognosis. Since the 1990s, substantial advances have been made in the use of circulating biomarkers for such assessments. This summary of the session on "Biomarkers: can they really use guide our daily practice?" presented at the 2021 WEB-CONFERENCE OF THE EUROPEAN SHOCK SOCIETY, 6 November 2021. These biomarkers include ultrasensitive detection of bacteremia, circulating soluble urokina-type plasminogen activator receptor (suPAR), C-reactive protein (CRP) and ferritin and procalcitonin. In addition, the potential application of novel multiwavelength optical biosensor technology allows noninvasive monitoring of multiple metabolites that can be used to assess severity and prognosis in septic patients. The application these biomarkers and improved technologies provide the potential for improved personalized management of septic patients. 10.1097/SHK.0000000000001957
Hyperferritinemia in the elderly can differentiate the bad from the worst: A retrospective cohort analysis. Medicine Both total-body iron stores and inflammation influence the concentration of ferritin in the blood. Ferritin as an inflammatory marker might serve as a prognostic marker in the elderly. Therefore, we characterized the clinical circumstances and long-term outcomes of hyperferritinemia (> 1000 μg/L) in hospitalized elderly patients.A retrospective analysis of elderly (> 70 years) inpatients with ferritin levels of > 1000 μg/L in a tertiary medical center during a 3-year period. We obtained both laboratory and clinical data, assessing the potential association of high ferritin levels with long-term mortality.Overall, 242 patients (median age 79 years; median ferritin level 1436 μg/L) met the inclusion criteria and were followed for a median time of 18.6 months. Clinical outcomes were dismal for the whole cohort: the diagnosis of solid malignancy occurred in 23.5% of cases while 31% had a severe infection (ranging from sepsis to septic shock). The median survival time of the whole cohort was 4.7 months only. Within the cohort, risk stratification was feasible: higher ferritin levels differentiate between groups of patients who had a poor prognosis (with either septic shock or solid malignancy) and those who had a relatively favorable prognosis (patients diagnosed as suffering from sepsis without shock and patients with iatrogenic causes for hyperferritinemia).Hyperferritinemia in elderly inpatients is associated with high rates of mortality. Within this group of patients, differential ferritin levels enable further risk stratification. High ferritin levels in the elderly can differentiate the bad from the worst. 10.1097/MD.0000000000021419
A single transcript for the prognosis of disease severity in COVID-19 patients. Lei Hongxing Scientific reports With many countries strapped for medical resources due to the COVID-19 pandemic, it is highly desirable to allocate the precious resources to those who need them the most. Several markers have been found to be associated with the disease severity in COVID-19 patients. However, the established markers only display modest prognostic power individually and better markers are urgently needed. The aim of this study is to investigate the potential of S100A12, a prominent marker gene for bacterial infection, in the prognosis of disease severity in COVID-19 patients. To ensure the robustness of the association, a total of 1695 samples from 14 independent transcriptome datasets on sepsis, influenza infection and COVID-19 infection were examined. First, it was demonstrated that S100A12 was a marker for sepsis and severity of sepsis. Then, S100A12 was found to be a marker for severe influenza infection, and there was an upward trend of S100A12 expression as the severity level of influenza infection increased. As for COVID-19 infection, it was found that S100A12 expression was elevated in patients with severe and critical COVID-19 infection. More importantly, S100A12 expression at hospital admission was robustly correlated with future quantitative indexes of disease severity and outcome in COVID-19 patients, superior to established prognostic markers including CRP, PCT, d-dimer, ferritin, LDH and fibrinogen. Thus, S100A12 is a valuable novel prognostic marker for COVID-19 severity and deserves more attention. 10.1038/s41598-021-91754-7
Ferritin, fever, and frequent visits: Hyperferritinemic syndromes in the emergency department. Annous Youssef,Manning Sara,Khoujah Danya The American journal of emergency medicine Fever of unknown origin (FUO) is defined as persistent fevers without an identifiable cause despite extensive medical workup. Emergency physicians caring for patients reporting a persistent, nonspecific, febrile illness should carefully consider potentially serious non-infectious causes of FUO. We present a case of a 35-year-old man who presented to the emergency department (ED) three times over a 10-day period for persistent febrile illness and was ultimately diagnosed with Adult-Onset Still's Disease (AOSD) after a serum ferritin level was found to be over 42,000 μg/L. AOSD, along with macrophage activation syndrome, catastrophic antiphospholipid syndrome, and septic shock comprise the four hyperferritinemic syndromes. These are potentially life-threatening febrile illnesses that characteristically present with elevated ferritin levels. In this article, we highlight the value of a serum ferritin level in the workup of a patient with prolonged febrile illness and its utility in facilitating early diagnosis and prompt treatment of hyperferritinemic syndromes in the ED. 10.1016/j.ajem.2021.04.088
Beneficial Immune Regulation by Biological Response Modifier Glucans in COVID-19 and Their Envisaged Potentials in the Management of Sepsis. Frontiers in immunology Sepsis is a life-threatening condition caused by an abnormal immune response induced by infection with no approved or specific therapeutic options. We present our perspectives for the therapeutic management of sepsis through a four-way approach: (1) infection control through immune enhancement; (2) immune suppression during the initial hyper-inflammatory phase; (3) balanced immune-modulation to counter the later immune-paralysis phase; and (4) advantageous effects on metabolic and coagulation parameters throughout. COVID-19 is a virus-triggered, accelerated sepsis-like reaction that is associated with the rapid progress of an inflammatory cascade involving a cytokine storm and multiorgan failure. Here, we discuss the potential of the biological response modifiers, β-glucans (BRMGs), in the management of sepsis based on their beneficial effects on inflammatory-immune events in COVID-19 clinical studies. In COVID-19 patients, apart from metabolic regulation, BRMGs, derived from a black yeast, strain AFO-202, have been reported to stimulate immune responses. BRMGs, produced by another strain (N-163) of , have been implicated in the beneficial regulation of inflammatory markers and immunity, namely IL-6, C-reactive protein (CRP), D-Dimer, ferritin, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-C-reactive protein ratio (LCR), leucocyte-to-C-reactive protein ratio (LeCR), and leukocyte-to-IL-6 ratio (LeIR). Agents such as these β-glucans, which are safe as they have been widely consumed by humans for decades, have potential as adjuncts for the prevention and management of sepsis as they exert their beneficial effects across the spectrum of processes and factors involved in sepsis pathology, including, but not limited to, metabolism, infection, inflammation, immune modulation, immune enhancement, and gut microbiota. 10.3389/fimmu.2022.870632
CD163 as a valuable diagnostic and prognostic biomarker of sepsis-associated hemophagocytic lymphohistiocytosis in critically ill children. Cui Yun,Xiong Xi,Ren Yuqian,Wang Fei,Wang Chunxia,Zhang Yucai Pediatric blood & cancer OBJECTIVE:To investigate CD163 as an effective biomarker for identifying and predicting the outcomes of sepsis-associated hemophagocytic lymphohistiocytosis (SAHS) in children. METHODS:We prospectively enrolled presumed sepsis patients who had developed prolonged fever (>7 days), hepatosplenomegaly, cytopenias, and hyperferritinemia (>500 ng/mL) despite antibiotic therapy. Blood samples were collected within 24 hours after enrolment. A nested case-control study was performed. The number of patients who fulfilled the HLH-2004 criteria, 28-day mortality outcomes, and 90-day mortality outcomes were recorded. RESULTS:Sixty-nine patients were enrolled in the study. Significant increases in the levels of ferritin and soluble CD163 (sCD163) and the percentage of CD163-positive peripheral blood mononuclear cells (mCD163) and decreases in fibrinogen levels and the percentage of natural killer cells (NK %) were observed in patients with SAHS (n = 23) compared with those of patients with sepsis (n = 46). The area under the ROC curve (AUC) for ferritin combined with sCD163 was superior to the AUC for either ferritin or sCD163 for distinguishing SAHS from sepsis. Moreover, sCD163 was a prognostic factor for 28-day mortality (0.857 [0.659-1.000]). CONCLUSIONS:sCD163 is a valuable biomarker for the differential diagnosis of SAHS from sepsis and effectively predicts 28-day mortality in children with SAHS. 10.1002/pbc.27909
Hepcidin and ferritin levels as markers of immune cell activation during septic shock, severe COVID-19 and sterile inflammation. Frontiers in immunology Introduction:Major clinically relevant inflammatory events such as septic shock and severe COVID-19 trigger dynamic changes in the host immune system, presenting promising candidates for new biomarkers to improve precision diagnostics and patient stratification. Hepcidin, a master regulator of iron metabolism, has been intensively studied in many pathologies associated with immune system activation, however these data have never been compared to other clinical settings. Thus, we aimed to reveal the dynamics of iron regulation in various clinical settings and to determine the suitability of hepcidin and/or ferritin levels as biomarkers of inflammatory disease severity. Cohorts:To investigate the overall predictive ability of hepcidin and ferritin, we enrolled the patients suffering with three different diagnoses - in detail 40 patients with COVID-19, 29 patients in septic shock and eight orthopedic patients who were compared to nine healthy donors and all cohorts to each other. Results:We showed that increased hepcidin levels reflect overall immune cell activation driven by intrinsic stimuli, without requiring direct involvement of infection vectors. Contrary to hepcidin, ferritin levels were more strongly boosted by pathogen-induced inflammation - in septic shock more than four-fold and in COVID-19 six-fold in comparison to sterile inflammation. We also defined the predictive capacity of hepcidin-to-ferritin ratio with AUC=0.79 and = 0.03. Discussion:Our findings confirm that hepcidin is a potent marker of septic shock and other acute inflammation-associated pathologies and demonstrate the utility of the hepcidin-to-ferritin ratio as a predictor of mortality in septic shock, but not in COVID-19. 10.3389/fimmu.2023.1110540
Biomarkers for Early Diagnosis of Hemophagocytic Lymphohistiocytosis in Critically Ill Patients. Debaugnies France,Mahadeb Bhavna,Nagant Carole,Meuleman Nathalie,De Bels David,Wolff Fleur,Gottignies Philippe,Salaroli Adriano,Borde Patricia,Voué Michel,Corazza Francis Journal of clinical immunology Many biomarkers have been proposed for the diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH) in adults, but comparative studies are lacking. We analyzed ferritin, glycosylated ferritin, soluble CD25, CD163 and CD14, IL-6, IFN-γ, IL-18, IL-10, IL-1ß, IL-12p70, IL-17α, IP-10, and CXCL9 levels to differentiate HLH from sepsis in critically ill patients. Of 120 patients, HLH was confirmed for 14 patients. Among the biomarkers tested, ferritin, IL-18, and glycosylated ferritin were the most efficient parameters for early diagnosis of HLH. With a sensitivity set at 85%, ferritin, IL-18, and glycosylated ferritin were the biomarkers with the highest specificity: 84, 79, and 71% respectively. Combining IL-18 with the HScore provided a new score with an increased specificity compared to the HScore alone, 86% compared to 70% with a sensitivity set at 100%. A distinct cytokine pattern was highlighted in patients with malignancy-triggered HLH, with highly increased levels of INF-ɣ and CXCL9, compared to HLH secondary to infection. This is the largest study available to date, comparing diagnostic biomarkers for HLH on a cohort of critically ill adult patients. Serum ferritin was the most discriminating parameter for early diagnosis of secondary HLH. IL18HScore was identified as a highly potential score. 10.1007/s10875-020-00950-z
Hyperferritinemia in children hospitalized with scrub typhus. Williams Vijai,Menon Nisha,Bhatia Prateek,Biswal Manisha,Sreedharanunni Sreejesh,Jayashree Muralidharan,Nallasamy Karthi Tropical medicine and health BACKGROUND:Hyperferritinemia is increasingly associated with mortality in sepsis. Studies estimating the prevalence of hyperferritinemia in pediatric scrub typhus are limited. METHODS:This was a secondary analysis of a prospective observational study (FERRIS) from a tertiary care teaching hospital in North India where 72 children with confirmed scrub typhus, 4 (5.5%) PCR positive, 55 (76.4%)-IgM ELISA positive, and 13 (18.1%)-both PCR and ELISA positive, were analyzed. Serum ferritin was measured in 62 children to identify the prevalence of hyperferritinemia and determine its association with mortality. RESULTS:Hyperferritinemia (> 500 μg/L) was seen in 72.6% [n = 45] children; 26 (41.9%) were mild (500-2000 μg/L), 13 (21%) were moderate (2000-10,000 μg/L), and 6 (9.7%) were severe (> 10,000 μg/L). Early presentation to hospital (≤ 7 days of febrile illness) had more survivors than late presentation (> 7 days). Non-survivors had significantly higher PRISM III, PELOD-2, hyperlactatemia, hypoalbuminemia, organ dysfunction, need for mechanical ventilation, and need of RRT. Ferritin had poor sensitivity and specificity in predicting survival with AUC of 0.56. Organ dysfunction and risk scores as PRISM III, PELOD 2, and VIS at admission were better predictors with AUC (95% CI) of 0.72 (0.56, 0.89), 0.77 (0.63, 0.92), and 0.90 (0.78, 1.0) respectively. CONCLUSIONS:Hyperferritinemia is common in scrub typhus but it did not predict survival. Organ dysfunction and risk scores were better predictors of mortality than ferritin. 10.1186/s41182-021-00304-4
Ferritin H deficiency deteriorates cellular iron handling and worsens Salmonella typhimurium infection by triggering hyperinflammation. JCI insight Iron is an essential nutrient for mammals as well as for pathogens. Inflammation-driven changes in systemic and cellular iron homeostasis are central for host-mediated antimicrobial strategies. Here, we studied the role of the iron storage protein ferritin H (FTH) for the control of infections with the intracellular pathogen Salmonella enterica serovar Typhimurium by macrophages. Mice lacking FTH in the myeloid lineage (LysM-Cre+/+Fthfl/fl mice) displayed impaired iron storage capacities in the tissue leukocyte compartment, increased levels of labile iron in macrophages, and an accelerated macrophage-mediated iron turnover. While under steady-state conditions, LysM-Cre+/+Fth+/+ and LysM-Cre+/+Fthfl/fl animals showed comparable susceptibility to Salmonella infection, i.v. iron supplementation drastically shortened survival of LysM-Cre+/+Fthfl/fl mice. Mechanistically, these animals displayed increased bacterial burden, which contributed to uncontrolled triggering of NF-κB and inflammasome signaling and development of cytokine storm and death. Importantly, pharmacologic inhibition of the inflammasome and IL-1β pathways reduced cytokine levels and mortality and partly restored infection control in iron-treated ferritin-deficient mice. These findings uncover incompletely characterized roles of ferritin and cellular iron turnover in myeloid cells in controlling bacterial spread and for modulating NF-κB and inflammasome-mediated cytokine activation, which may be of vital importance in iron-overloaded individuals suffering from severe infections and sepsis. 10.1172/jci.insight.141760
Adiponectin as a sepsis biomarker in dogs: Diagnostic and prognostic value. Torrente Carlos,Manzanilla Edgar G,Bosch Luis,Villaverde Cecilia,Pastor Josep,Ruiz de Gopegui Rafael,Tvarijonaviciute Asta Veterinary clinical pathology BACKGROUND:Adiponectin (ADPN) is an adipocytokine with insulin-sensitizing, vascular-protective, and anti-inflammatory properties for which concentration changes occur in response to inflammation. Little is known about the regulation of ADPN and the impact of this adipocytokine in septic dogs. OBJECTIVE:We aimed to assess the diagnostic and prognostic value of ADPN vs other traditional acute-phase proteins (APPs), such as albumin (ALB), haptoglobin (HPT), fibrinogen (FBG), ferritin (FRT), and C-reactive protein (CRP) in dogs with naturally acquired sepsis. METHODS:This prospective observational study included 20 dogs with sepsis, 27 with low-grade systemic inflammation (LGSI), and 18 clinically healthy dogs as controls. For method analyses, plasma samples were obtained from all dogs on admission and then every 24-48 hours until discharge or death in the septic group. RESULTS:Septic dogs had lower ADPN (2.4 ± 0.46 vs 4.5 ± 0.41mg/L, P < .001) dand ALB (17 ± 1 vs 22 ± 0.8g/L, P = .002), and tended to have higher CRP (87 ± 4.8 vs 73 ± 4.1mg/L, P < .079) concentrations than dogs with LGSI on admission. Only ADPN and ALB were able to successfully discriminate animals with LGSI from those presenting with sepsis with areas under the curve (AUCs) for the receiver operating characteristic (ROC) curves of 0.811 and 0.789, respectively. In the septic group, ADPN concentration did not differ between survivors and non-survivors, either on admission or at discharge or death. CONCLUSIONS:Although plasma ADPN can be used as a reliable negative APP in dogs with sepsis, further studies are warranted to confirm the usefulness of this biomarker in terms of disease progression and recovery. 10.1111/vcp.12858
Serum Ferritin for Predicting Outcome in Children With Severe Sepsis in the Pediatric Intensive Care Unit. Indian pediatrics OBJECTIVES:To evaluate the prognostic ability of serum ferritin when estimated within 5 days of onset of illness in children with severe sepsis admitted to a pediatric intensive care unit. METHODS:This observational study enrolled children aged 1 month to 12 years with severe sepsis. Hemoglobin, serum ferritin and C-reactive protein levels were measured within five days of illness. Final outcomes were recorded in all enrolled children. RESULTS:70 children with median (IQR) age of 27 (8,108) months were enrolled during the study period (July, 2019 to August, 2021). 28 (40%) of these had poor outcome (non-survival). The median (IQR) level of serum ferritin was 1369 (558-5607) ng/mL in non-survivors and 282 (129-680) ng/mL in survivors (P<0.05). A significant correlation was seen between serum ferritin and Pediatric Risk of Mortality III (PRISM III) score (r=0.364 P=0.002) and pediatric Sequential Organ Failure Assessment (pSOFA) score (r=0.246 P=0.04) at 48 hours of admission. 54 (77.1%) children were anemic. Serum ferritin levels in children with anemia also had a good predictive ability for poor outcome [AUC: 0.764, 95% CI: 0.634, 0.894]. CONCLUSIONS:Serum ferritin levels, within five days of onset of illness, predicted poor outcome in critically ill children with severe sepsis and in children with microcytic anemia.
Haemophagocytic lymphohistiocytosis in adult critical care. Bauchmuller Kris,Manson Jessica J,Tattersall Rachel,Brown Michael,McNamara Christopher,Singer Mervyn,Brett Stephen J Journal of the Intensive Care Society Haemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune dysregulation, characterised by extreme inflammation, fever, cytopaenias and organ dysfunction. HLH can be triggered by conditions such as infection, autoimmune disease and malignancy, among others. Both a familial and a secondary form have been described, the latter being increasingly recognised in adult patients with critical illness. HLH is difficult to diagnose, often under-recognised and carries a high mortality. Patients can present in a very similar fashion to sepsis and the two syndromes can co-exist and overlap, yet HLH requires specific immunosuppressive therapy. HLH should be actively excluded in patients with presumed sepsis who either lack a clear focus of infection or who are not responding to energetic infection management. Elevated serum ferritin is a key biomarker that may indicate the need for further investigations for HLH and can guide treatment. Early diagnosis and a multidisciplinary approach to HLH management may save lives. 10.1177/1751143719893865
Ferritin regulates organismal energy balance and thermogenesis. Blankenhaus Birte,Braza Faouzi,Martins Rui,Bastos-Amador Patricia,González-García Ismael,Carlos Ana Rita,Mahu Inês,Faisca Pedro,Nunes Jose Moura,Ventura Pedro,Hoerr Verena,Weis Sebastian,Guerra Joel,Cardoso Silvia,Domingos Ana,López Miguel,Soares Miguel P Molecular metabolism OBJECTIVE:The ferritin heavy/heart chain (FTH) gene encodes the ferroxidase component of the iron (Fe) sequestering ferritin complex, which plays a central role in the regulation of cellular Fe metabolism. Here we tested the hypothesis that ferritin regulates organismal Fe metabolism in a manner that impacts energy balance and thermal homeostasis. METHODS:We developed a mouse strain, referred herein as Fth, expressing a tamoxifen-inducible Cre recombinase under the control of the Rosa26 (R26) promoter and carrying two LoxP (fl) sites: one at the 5'end of the Fth promoter and another the 3' end of the first Fth exon. Tamoxifen administration induces global deletion of Fth in adult Fth mice, testing whether FTH is required for maintenance of organismal homeostasis. RESULTS:Under standard nutritional Fe supply, Fth deletion in adult Fth mice led to a profound deregulation of organismal Fe metabolism, oxidative stress, inflammation, and multi-organ damage, culminating in death. Unexpectedly, Fth deletion was also associated with a profound atrophy of white and brown adipose tissue as well as with collapse of energy expenditure and thermogenesis. This was attributed mechanistically to mitochondrial dysfunction, as assessed in the liver and in adipose tissue. CONCLUSION:The FTH component of ferritin acts as a master regulator of organismal Fe homeostasis, coupling nutritional Fe supply to organismal redox homeostasis, energy expenditure and thermoregulation. 10.1016/j.molmet.2019.03.008
Differential Diagnosis of Hyperferritinemia in Critically Ill Patients. Journal of clinical medicine BACKGROUND:Elevated serum ferritin is a common condition in critically ill patients. It is well known that hyperferritinemia constitutes a good biomarker for hemophagocytic lymphohistiocytosis (HLH) in critically ill patients. However, further differential diagnoses of hyperferritinemia in adult critically ill patients remain poorly investigated. We sought to systematically investigate hyperferritinemia in adult critically ill patients without HLH. METHODS:In this secondary analysis of a retrospective observational study, patients ≥18 years admitted to at least one adult intensive care unit at Charité-Universitätsmedizin Berlin between January 2006 and August 2018, and with hyperferritinemia of ≥500 μg/L were included. Patients with HLH were excluded. All patients were categorized into non-sepsis, sepsis, and septic shock. They were also classified into 17 disease groups, based on their ICD-10 codes, and pre-existing immunosuppression was determined. Uni- and multivariable linear regression analyses were performed in all patients. RESULTS:A total of 2583 patients were analyzed. Multivariable linear regression analysis revealed positive associations of maximum SOFA score, sepsis or septic shock, liver disease (except hepatitis), and hematological malignancy with maximum ferritin. T/NK cell lymphoma, acute myeloblastic leukemia, Kaposi's sarcoma, acute or subacute liver failure, and hepatic veno-occlusive disease were positively associated with maximum ferritin in post-hoc multivariable linear regression analysis. CONCLUSIONS:Sepsis or septic shock, liver disease (except hepatitis) and hematological malignancy are important differential diagnoses in hyperferritinemic adult critically ill patients without HLH. Together with HLH, they complete the quartet of important differential diagnoses of hyperferritinemia in adult critically ill patients. As these conditions are also related to HLH, it is important to apply HLH-2004 criteria for exclusion of HLH in hyperferritinemic patients. Hyperferritinemic critically ill patients without HLH require quick investigation of differential diagnoses. 10.3390/jcm12010192
Performance of prognostic markers in pediatric sepsis. Jornal de pediatria OBJECTIVE:To evaluate the prognostic performance of the Pediatric Index of Mortality 2 (PIM2), ferritin, lactate, C-reactive protein (CRP), and leukocytes, alone and in combination, in pediatric patients with sepsis admitted to the pediatric intensive care unit (PICU). METHODS:A retrospective study was conducted in a PICU in Brazil. All patients aged 6 months to 18 years admitted with a diagnosis of sepsis were eligible for inclusion. Those with ferritin and C-reactive protein measured within 48h and lactate and leukocytes within 24h of admission were included in the prognostic performance analysis. RESULTS:Of 350 eligible patients with sepsis, 294 had undergone all measurements required for analysis and were included in the study. PIM2, ferritin, lactate, and CRP had good discriminatory power for mortality, with PIM2 and ferritin being superior to CRP. The cutoff values for PIM2 (> 14%), ferritin (> 135ng/mL), lactate (> 1.7mmol/L), and CRP (> 6.7mg/mL) were associated with mortality. The combination of ferritin, lactate, and CRP had a positive predictive value of 43% for mortality, similar to that of PIM2 alone (38.6%). The combined use of the three biomarkers plus PIM2 increased the positive predictive value to 76% and accuracy to 0.945. CONCLUSIONS:PIM2, ferritin, lactate, and CRP alone showed good prognostic performance for mortality in pediatric patients older than 6 months with sepsis. When combined, they were able to predict death in three-fourths of the patients with sepsis. Total leukocyte count was not useful as a prognostic marker. 10.1016/j.jped.2020.07.008
Effect of Serum Ferritin on the Prognosis of Patients with Sepsis: Data from the MIMIC-IV Database. Emergency medicine international Background:The present study aimed to investigate the prognostic value of serum ferritin in critically ill patients with sepsis by using the MIMIC-IV database. Methods:Data were extracted from the MIMIC-IV database. Adult patients who met the sepsis-3 criteria and had the test of ferritin were included. Patients were divided into subgroups according to the initial serum ferritin. The association between initial serum ferritin and in-hospital mortality was performed by using Lowessregression, logistic regression, and ROC analysis. Subgroup analysis was used to search for the interacting factors and verify the robustness of the results. Results:Analysis of the 2,451 patients revealed a positive linear relationship between serum ferritin and in-hospital mortality. Patients with high-ferritin had a higher risk of in-hospital mortality, but no significant association was found in the low-ferritin subgroup compared with those whose ferritin was in the normal reference range. Serum ferritin had moderate predictive power for in-hospital mortality (AUC = 0.651), with an optimal cut-off value of 591.5 ng/ml. Ferritin ≥591.5 ng/ml acted as an independent prognostic predictor of in-hospital mortality, which increased the risk of in-hospital mortality by 119%. Our findings were still robust in subgroup analysis, and acute kidney injury and anemia were considered interactive factors. Conclusion:High-level serum ferritin was an independent prognostic marker for the prediction of mortality in patients with sepsis. Further high-quality research is needed to confirm the relationship between ferritin and the prognosis of septic patients. 10.1155/2022/2104755
Serum Ferritin as a Diagnostic Biomarker for Severity of Childhood Sepsis. Nandy Arnab,Mondal Tanushree,Datta Debadyuti,Ray Somosri,Kumar Nitis,Ivan M Divyoshanu,Hazra Avijit,Mondal Rakesh Indian pediatrics OBJECTIVE:To explore association between serum ferritin and severity of sepsis among children, and relate levels to the final outcome. METHODS:This observational study was conducted in a tertiary care hospital between I February and 30 July, 2019. Serum ferritin level was estimated in children (age 6 months to 12 years) suffering from sepsis, irrespective of the probable etiology. Children with hemoglobinopathies, autoimmune diseases, previous blood transfusion, severe acute malnutrition, hemophagocytic lymphohistiocytosis and chronic hepatitis were excluded. The ferritin level was measured sequentially at pre-defined stages of illness viz., sepsis, severe sepsis, septic shock and multiorgan dysfunction syndrome (MODS). Association between serum ferritin and severity of sepsis was analyzed, and ferritin level was related to the final outcome of death or recovery by receiver operating characteristic (ROC) curve analysis. RESULTS:The study group included 47 children with sepsis who progressed to a state of MODS; 32 recovered from MODS. Significant differences in serum ferritin level were observed with severity of sepsis. There was clear demarcation of ferritin levels between sepsis severity stages. The proportion of death among the 47 MODS cases was 31.9% (95% CI 18.6 - 45.2%). ROC analysis in the MODS group indicated that serum ferritin >1994.3 ng/mL predicts mortality (AUC 0.73 [95% CI 0.58-0.85]) with sensitivity 66.7% [95% CI 38.4-88%] and specificity 100.0% [95% CI 89.1-100%]. CONCLUSIONS:There is clear demarcation of serum ferritin levels that can help differentiation of sepsis severity stages in children with sepsis. There is no such demarcation between survivors and non-survivors in MODS cases.
Hyperferritinemia in Critically Ill Patients. Critical care medicine OBJECTIVE:Hyperferritinemia is frequently seen in critically ill patients. A rather rare though life-threatening condition related to severely elevated ferritin is hemophagocytic lymphohistiocytosis. We analyze ferritin levels to differentiate hemophagocytic lymphohistiocytosis from other causes of hyperferritinemia in a mixed cohort of critically ill patients. DESIGN:Retrospective observational study. SETTING:Adult surgical, anesthesiologic, and medical ICUs of a university hospital. PATIENTS:Critical care patients (≥ 18 yr old) admitted to any of the adult ICUs at Charité - Universitätsmedizin Berlin between January 2006 and August 2018 with at least one ferritin value and hyperferritinemia (≥ 500 µg/L). INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Patients were categorized into hemophagocytic lymphohistiocytosis, sepsis, septic shock, and other diagnoses. These were further categorized into 17 subgroups. Hemophagocytic lymphohistiocytosis diagnosis was based on Hemophagocytic Lymphohistiocytosis-2004 criteria and the HScore. Of 2,623 patients with hyperferritinemia, 40 were considered to have hemophagocytic lymphohistiocytosis (1.52%). Maximum ferritin levels were highest in hemophagocytic lymphohistiocytosis patients compared with all other disease groups (each p < 0.001). Sepsis and septic shock patients had higher maximum ferritin levels than patients with other diagnoses (each p < 0.001). A maximum ferritin value of 9,083 µg/L was at 92.5% sensitivity and 91.9% specificity for hemophagocytic lymphohistiocytosis (area under the curve, 0.963; 95% CI, 0.949-0.978). Of all subgroups with other diagnoses, maximum ferritin levels were highest in patients with varicella-zoster virus, hepatitis, or malaria (median, 1,935, 1,928, and 1,587 µg/L, respectively). Maximum ferritin levels were associated with increased in-hospital mortality (odds ratio, 1.518 per log µg/L [95% CI, 1.384-1.665 per log µg/L]; p < 0.001). CONCLUSIONS:This is the largest study of patients with ferritin available in a mixed ICU cohort. Ferritin levels in patients with hemophagocytic lymphohistiocytosis, sepsis, septic shock, and other conditions were distinctly different, with the highest ferritin levels observed in hemophagocytic lymphohistiocytosis patients. Maximum ferritin of 9,083 µg/L showed high sensitivity and specificity and, therefore, may contribute to improved diagnosis of hemophagocytic lymphohistiocytosis in ICU. The inclusion of ferritin into the sepsis laboratory panel is warranted. 10.1097/CCM.0000000000004131
Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysis. The Lancet. Rheumatology BACKGROUND:Anakinra might improve the prognosis of patients with moderate to severe COVID-19 (ie, patients requiring oxygen supplementation but not yet receiving organ support). We aimed to assess the effect of anakinra treatment on mortality in patients admitted to hospital with COVID-19. METHODS:For this systematic review and individual patient-level meta-analysis, a systematic literature search was done on Dec 28, 2020, in Medline (PubMed), Cochrane, medRxiv, bioRxiv, and the ClinicalTrials.gov databases for randomised trials, comparative studies, and observational studies of patients admitted to hospital with COVID-19, comparing administration of anakinra with standard of care, or placebo, or both. The search was repeated on Jan 22, 2021. Individual patient-level data were requested from investigators and corresponding authors of eligible studies; if individual patient-level data were not available, published data were extracted from the original reports. The primary endpoint was mortality after 28 days and the secondary endpoint was safety (eg, the risk of secondary infections). This study is registered on PROSPERO (CRD42020221491). FINDINGS:209 articles were identified, of which 178 full-text articles fulfilled screening criteria and were assessed. Aggregate data on 1185 patients from nine studies were analysed, and individual patient-level data on 895 patients were provided from six of these studies. Eight studies were observational and one was a randomised controlled trial. Most studies used historical controls. In the individual patient-level meta-analysis, after adjusting for age, comorbidities, baseline ratio of the arterial partial oxygen pressure divided by the fraction of inspired oxygen (PaO/FiO), C-reactive protein (CRP) concentrations, and lymphopenia, mortality was significantly lower in patients treated with anakinra (38 [11%] of 342) than in those receiving standard of care with or without placebo (137 [25%] of 553; adjusted odds ratio [OR] 0·32 [95% CI 0·20-0·51]). The mortality benefit was similar across subgroups regardless of comorbidities (ie, diabetes), ferritin concentrations, or the baseline PaO/FiO. In a subgroup analysis, anakinra was more effective in lowering mortality in patients with CRP concentrations higher than 100 mg/L (OR 0·28 [95% CI 0·17-0·47]). Anakinra showed a significant survival benefit when given without dexamethasone (OR 0·23 [95% CI 0·12-0·43]), but not with dexamethasone co-administration (0·72 [95% CI 0·37-1·41]). Anakinra was not associated with a significantly increased risk of secondary infections when compared with standard of care (OR 1·35 [95% CI 0·59-3·10]). INTERPRETATION:Anakinra could be a safe, anti-inflammatory treatment option to reduce the mortality risk in patients admitted to hospital with moderate to severe COVID-19 pneumonia, especially in the presence of signs of hyperinflammation such as CRP concentrations higher than 100 mg/L. FUNDING:Sobi. 10.1016/S2665-9913(21)00216-2
The relationship between serum ferritin level and clinical outcomes in sepsis based on a large public database. Scientific reports This study aimed to investigate the relationship between serum ferritin level and prognosis in sepsis. It also explored the potential prognostic value of serum ferritin for predicting outcomes in sepsis based on a large public database. Sepsis patients in MIMIC-IV database were included. Different models including crude model (adjusted for none), model I (adjusted for age and gender) and model II (adjusted for all potential confounders) were performed. Smooth fitting curves were constructed for exploring the relationships between serum ferritin and mortalities of 28-day, 90-day, 180-day and 1-year. Receiver operator characteristic (ROC) curve analysis was utilized for assessing the predictive value of serum ferritin. 1947 sepsis patients were included. The mortalities of 28-day, 90-day, 180-day and 1-year were 20.18% (n = 393), 28.35% (n = 552), 30.30% (n = 590) and 31.54% (n = 614), respectively. In Model II (adjusted for all potential confounders), for every 1000 ng/ml increment in serum ferritin, the values of OR in mortalities of in 28-day, 90-day, 180-day and 1-year were 1.13 (95% CI 1.07-1.19, P < 0.0001), 1.15 (95% CI 1.09-1.21, P < 0.0001), 1.16 (95% CI 1.10-1.22, P < 0.0001) and 1.17 (95% CI 1.10-1.23, P < 0.0001), respectively. The relationships between serum ferritin level and outcomes were non-linear. The areas under the ROC curve (AUC) of ferritin for predicting mortalities of 28-day, 90-day, 180-day and 1-year were 0.597 (95% CI 0.563-0.629), 0.593 (95% CI 0.564-0.621), 0.595 (95% CI 0.567-0.623) and 0.592 (95% CI 0.564-0.620), respectively. The non-linear relationships between serum ferritin and clinical outcomes in sepsis were found. Serum ferritin had a predictive value for short-term and long-term outcomes in sepsis. 10.1038/s41598-023-35874-2
Hyperferritinaemia: An Iron Sword of Autoimmunity. Giemza-Stokłosa Joanna,Islam Md Asiful,Kotyla Przemysław J Current pharmaceutical design BACKGROUND:Ferritin is a molecule that plays many roles being the storage for iron, signalling molecule, and modulator of the immune response. METHODS:Different electronic databases were searched in a non-systematic way to find out the literature of interest. RESULTS:The level of ferritin rises in many inflammatory conditions including autoimmune disorders. However, in four inflammatory diseases (i.e., adult-onset Still's diseases, macrophage activation syndrome, catastrophic antiphospholipid syndrome, and sepsis), high levels of ferritin are observed suggesting it as a remarkable biomarker and pathological involvement in these diseases. Acting as an acute phase reactant, ferritin is also involved in the cytokine-associated modulator of the immune response as well as a regulator of cytokine synthesis and release which are responsible for the inflammatory storm. CONCLUSION:This review article presents updated information on the role of ferritin in inflammatory and autoimmune diseases with an emphasis on hyperferritinaemic syndrome. 10.2174/1381612825666190709202804
Why and How Is Hyperferritinemic Sepsis Different From Sepsis Without Hyperferritinemia? Carcillo Joseph A,Kernan Kate K,Horvat Christopher M,Simon Dennis W,Aneja Rajesh K Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 10.1097/PCC.0000000000002285
A study on biomarkers of sepsis and potential role of procalcitonin and ferritin marker in diagnosis, prognosis and treatment. Journal of family medicine and primary care Objectives:To evaluate the potential value of serum procalcitonin and serum ferritin levels in patients with clinically suspected and proven sepsis and their comparison with established inflammatory markers like C-reactive protein (CRP) and total leukocyte count. Materials and Methods:A total of 60 clinically suspected cases of sepsis were included in this study and each patient was investigated for serum S. ferritin, procalcitonin, and CRP and blood cultures using the BacT/Alert system. Results:Serum procalcitonin at a cut-off value of >2 ng/ml is a valuable biomarker for early diagnosis in sepsis patients due to bacterial infection and has a greater predictive value than serum ferritin, CRP, or any other biomarkers. 10.4103/jfmpc.jfmpc_1920_21
Ferritin Light Chain Confers Protection Against Sepsis-Induced Inflammation and Organ Injury. Frontiers in immunology Despite the prevalence and recognition of its detrimental impact, clinical complications of sepsis remain a major challenge. Here, we investigated the effects of myeloid ferritin heavy chain (FtH) in regulating the pathogenic sequelae of sepsis. We demonstrate that deletion of myeloid FtH leads to protection against lipopolysaccharide-induced endotoxemia and cecal ligation and puncture (CLP)-induced model of sepsis as evidenced by reduced cytokine levels, multi-organ dysfunction and mortality. We identified that such protection is predominantly mediated by the compensatory increase in circulating ferritin (ferritin light chain; FtL) in the absence of myeloid FtH. Our and studies indicate that prior exposure to ferritin light chain restrains an otherwise dysregulated response to infection. These findings are mediated by an inhibitory action of FtL on NF-κB activation, a key signaling pathway that is implicated in the pathogenesis of sepsis. We further identified that LPS mediated activation of MAPK pathways, specifically, JNK, and ERK were also reduced with FtL pre-treatment. Taken together, our findings elucidate a crucial immunomodulatory function for circulating ferritin that challenges the traditional view of this protein as a mere marker of body iron stores. Accordingly, these findings will stimulate investigations to the adaptive nature of this protein in diverse clinical settings. 10.3389/fimmu.2019.00131
Mortality Risk in Pediatric Sepsis Based on C-reactive Protein and Ferritin Levels. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies OBJECTIVES:Interest in using bedside C-reactive protein (CRP) and ferritin levels to identify patients with hyperinflammatory sepsis who might benefit from anti-inflammatory therapies has piqued with the COVID-19 pandemic experience. Our first objective was to identify patterns in CRP and ferritin trajectory among critically ill pediatric sepsis patients. We then examined the association between these different groups of patients in their inflammatory cytokine responses, systemic inflammation, and mortality risks. DATA SOURCES:A prospective, observational cohort study. STUDY SELECTION:Children with sepsis and organ failure in nine pediatric intensive care units in the United States. DATA EXTRACTION:Two hundred and fifty-five children were enrolled. Five distinct clinical multi-trajectory groups were identified. Plasma CRP (mg/dL), ferritin (ng/mL), and 31 cytokine levels were measured at two timepoints during sepsis (median Day 2 and Day 5). Group-based multi-trajectory models (GBMTM) identified groups of children with distinct patterns of CRP and ferritin. DATA SYNTHESIS:Group 1 had normal CRP and ferritin levels ( n = 8; 0% mortality); Group 2 had high CRP levels that became normal, with normal ferritin levels throughout ( n = 80; 5% mortality); Group 3 had high ferritin levels alone ( n = 16; 6% mortality); Group 4 had very high CRP levels, and high ferritin levels ( n = 121; 11% mortality); and Group 5 had very high CRP and very high ferritin levels ( n = 30; 40% mortality). Cytokine responses differed across the five groups, with ferritin levels correlated with macrophage inflammatory protein 1α levels and CRP levels reflective of many cytokines. CONCLUSIONS:Bedside CRP and ferritin levels can be used together to distinguish groups of children with sepsis who have different systemic inflammation cytokine responses and mortality risks. These data suggest future potential value in personalized clinical trials with specific targets for anti-inflammatory therapies. 10.1097/PCC.0000000000003074
Differences in inflammatory markers between coronavirus disease 2019 and sepsis in hospitalised patients. Clinical epidemiology and global health Background:Inflammatory markers are pivotal for the diagnosis of coronavirus disease 2019 (COVID-19) and sepsis. This study compared markers between hospitalised patients with COVID-19 and those with bacterial sepsis. Methods:This retrospective single-centre cohort study included 50 patients with COVID-19 clinical stages II and III and 24 patients with bacterial sepsis. Both groups were treated according to the country's official standards. Leukocytes, C-reactive protein (CRP), ferritin, and D-dimer were registered at the time of patient's admission and 24, 48, and 72 h after initiating intrahospital treatment. Results:Upon admission, marker levels were high, with a significant decrease at 72 h after antibiotic therapy in the sepsis group. The leukocyte count was higher in deceased patients with sepsis. The mean ferritin levels were 1105 mcg/dl for COVID-19 and 525 mcg/dL for sepsis. Higher ferritin levels in COVID-19 ( = 0.001) seemed to be a predictor of higher mortality. Upon admission, the median D-dimer level was 0.68 mg/L for COVID-19 and 3 mg/L for patients with sepsis, whether recovered or deceased. As D-dimer, procalcitonin levels were higher in patients with sepsis ( = 0.001). CRP levels were equally elevated in both entities but higher in deceased patients with COVID-19. Conclusion:Ferritin was the main inflammatory marker for COVID-19, and leukocytes, procalcitonin, and D-dimer were the main markers of sepsis. Markers that were most affected in deceased patients were CRP for COVID-19 and leukocyte for sepsis. The therapeutic implications of these differences require further study. 10.1016/j.cegh.2022.101059
Monitoring immunomodulation in patients with sepsis. Kyriazopoulou Evdoxia,Giamarellos-Bourboulis Evangelos J Expert review of molecular diagnostics : This review aims to summarize current progress of the last ten years in the development of biomarkers used for classifying the immune response of the septic host and for monitoring the efficacy of the applied adjunctive immunotherapy.: An extensive search of the literature was performed. In this review the authors discuss available biomarkers of host immune response in sepsis toward two directions; immunosuppression and hyperinflammation. Ferritin, sCD163, sIL-2 ra, and IL-18 may help in the diagnosis of macrophage activation syndrome (MAS) complicating sepsis whereas lymphopenia, decreased HLA-DR expression on monocytes, overexpression of Programmed cell death protein-1 (PD-1)/Programmed death-ligand 1 (PD-L1) and IL-10 are indicators of sepsis-induced immunosuppression. Novel approaches in the classification of immune state in sepsis include Myeloid-Derived Suppressor Cells (MDSC) and specific endotypes, defined by gene expression and molecular techniques.: HLA-DR and ferritin are the most commonly used biomarkers to monitor immunomodulation in clinical practice whereas developing specific sepsis endotypes is the future target. New immunotherapy trials in sepsis need to incorporate biomarkers for a personalized treatment. 10.1080/14737159.2020.1851199