ABSTRACT
OBJECTIVE: Subjective illness perception (IP) can differ from physician's clinical assessment results. Herein, we explored patient's IP during coronavirus disease 2019 (COVID-19) recovery. METHODS: Participants of the prospective observation CovILD study (ClinicalTrials.gov: NCT04416100) with persistent somatic symptoms or cardiopulmonary findings one year after COVID-19 were analyzed (n = 74). Explanatory variables included demographic and comorbidity, COVID-19 course and one-year follow-up data of persistent somatic symptoms, physical performance, lung function testing, chest computed tomography and trans-thoracic echocardiography. Factors affecting IP (Brief Illness Perception Questionnaire) one year after COVID-19 were identified by regularized modeling and unsupervised clustering. RESULTS: In modeling, 33% of overall IP variance (R2) was attributed to fatigue intensity, reduced physical performance and persistent somatic symptom count. Overall IP was largely independent of lung and heart findings revealed by imaging and function testing. In clustering, persistent somatic symptom count (Kruskal-Wallis test: η2 = 0.31, p < .001), fatigue (η2 = 0.34, p < .001), diminished physical performance (χ2 test, Cramer V effect size statistic: V = 0.51, p < .001), dyspnea (V = 0.37, p = .006), hair loss (V = 0.57, p < .001) and sleep problems (V = 0.36, p = .008) were strongly associated with the concern, emotional representation, complaints, disease timeline and consequences IP dimensions. CONCLUSION: Persistent somatic symptoms rather than abnormalities in cardiopulmonary testing influence IP one year after COVID-19. Modifying IP represents a promising innovative approach to treatment of post-COVID-19 condition. Besides COVID-19 severity, individual IP should guide rehabilitation and psychological therapy decisions.
Subject(s)
COVID-19 , Medically Unexplained Symptoms , Humans , Prospective Studies , Cross-Sectional Studies , Perception , Fatigue/etiologyABSTRACT
Background: Recovery trajectories from coronavirus disease 2019 (COVID-19) call for longitudinal investigation. We aimed to characterise the kinetics and status of clinical, cardiopulmonary and mental health recovery up to 1â year following COVID-19. Methods: Clinical evaluation, lung function testing (LFT), chest computed tomography (CT) and transthoracic echocardiography were conducted at 2, 3, 6 and 12â months after disease onset. Submaximal exercise capacity, mental health status and quality of life were assessed at 12â months. Recovery kinetics and patterns were investigated by mixed-effect logistic modelling, correlation and clustering analyses. Risk of persistent symptoms and cardiopulmonary abnormalities at the 1-year follow-up were modelled by logistic regression. Findings: Out of 145 CovILD study participants, 108 (74.5%) completed the 1-year follow-up (median age 56.5â years; 59.3% male; 24% intensive care unit patients). Comorbidities were present in 75% (n=81). Key outcome measures plateaued after 180â days. At 12â months, persistent symptoms were found in 65% of participants; 33% suffered from LFT impairment; 51% showed CT abnormalities; and 63% had low-grade diastolic dysfunction. Main risk factors for cardiopulmonary impairment included pro-inflammatory and immunological biomarkers at early visits. In addition, we deciphered three recovery clusters separating almost complete recovery from patients with post-acute inflammatory profile and an enrichment in cardiopulmonary residuals from a female-dominated post-COVID-19 syndrome with reduced mental health status. Conclusion: 1â year after COVID-19, the burden of persistent symptoms, impaired lung function, radiological abnormalities remains high in our study population. Yet, three recovery trajectories are emerging, ranging from almost complete recovery to post-COVID-19 syndrome with impaired mental health.
ABSTRACT
Anemia is a major health issue and associated with increased morbidity. Iron deficiency anemia (IDA) is the most prevalent, followed by anemia of chronic disease (ACD). IDA and ACD often co-exist, challenging diagnosis and treatment. While iron supplementation is the first-line therapy for IDA, its optimal route of administration and the efficacy of different repletion strategies in ACD are elusive. Female Lewis rats were injected with group A streptococcal peptidoglycan-polysaccharide (PG-APS) to induce inflammatory arthritis with associated ACD and/or repeatedly phlebotomized and fed with a low iron diet to induce IDA, or a combination thereof (ACD/IDA). Iron was either supplemented by daily oral gavage of ferric maltol or by weekly intravenous (i.v.) injection of ferric carboxymaltose for up to 4 weeks. While both strategies reversed IDA, they remained ineffective to improve hemoglobin (Hb) levels in ACD, although oral iron showed slight amelioration of various erythropoiesis-associated parameters. In contrast, both iron treatments significantly increased Hb in ACD/IDA. In ACD and ACD/IDA animals, i.v. iron administration resulted in iron trapping in liver and splenic macrophages, induction of ferritin expression and increased circulating levels of the iron hormone hepcidin and the inflammatory cytokine interleukin-6, while oral iron supplementation reduced interleukin-6 levels. Thus, oral and i.v. iron resulted in divergent effects on systemic and tissue iron homeostasis and inflammation. Our results indicate that both iron supplements improve Hb in ACD/IDA, but are ineffective in ACD with pronounced inflammation, and that under the latter condition, i.v. iron is trapped in macrophages and may enhance inflammation.
Subject(s)
Anemia, Iron-Deficiency , Anemia , Female , Animals , Rats , Interleukin-6 , Rats, Inbred Lew , Anemia/diagnosis , Iron/metabolism , Anemia, Iron-Deficiency/drug therapy , Anemia, Iron-Deficiency/etiology , Anemia, Iron-Deficiency/diagnosis , Inflammation/drug therapyABSTRACT
Iron is an essential component for metabolic processes, including oxygen transport within hemoglobin, tricarboxylic acid (TCA) cycle activity, and mitochondrial energy transformation. Iron deficiency can thus lead to metabolic dysfunction and eventually result in iron deficiency anemia (IDA), which affects approximately 1.5 billion people worldwide. Using a rat model of IDA induced by phlebotomy, we studied the effects of IDA on mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) and the liver. Furthermore, we evaluated whether the mitochondrial function evaluated by high-resolution respirometry in PBMCs reflects corresponding alterations in the liver. Surprisingly, mitochondrial respiratory capacity was increased in PBMCs from rats with IDA compared to the controls. In contrast, mitochondrial respiration remained unaffected in livers from IDA rats. Of note, citrate synthase activity indicated an increased mitochondrial density in PBMCs, whereas it remained unchanged in the liver, partly explaining the different responses of mitochondrial respiration in PBMCs and the liver. Taken together, these results indicate that mitochondrial function determined in PBMCs cannot serve as a valid surrogate for respiration in the liver. Metabolic adaptions to iron deficiency resulted in different metabolic reprogramming in the blood cells and liver tissue.
ABSTRACT
BACKGROUND: After the 2002/2003 severe acute respiratory syndrome outbreak, 30% of survivors exhibited persisting structural pulmonary abnormalities. The long-term pulmonary sequelae of coronavirus disease 2019 (COVID-19) are yet unknown, and comprehensive clinical follow-up data are lacking. METHODS: In this prospective, multicentre, observational study, we systematically evaluated the cardiopulmonary damage in subjects recovering from COVID-19 at 60 and 100â days after confirmed diagnosis. We conducted a detailed questionnaire, clinical examination, laboratory testing, lung function analysis, echocardiography and thoracic low-dose computed tomography (CT). RESULTS: Data from 145 COVID-19 patients were evaluated, and 41% of all subjects exhibited persistent symptoms 100â days after COVID-19 onset, with dyspnoea being most frequent (36%). Accordingly, patients still displayed an impaired lung function, with a reduced diffusing capacity in 21% of the cohort being the most prominent finding. Cardiac impairment, including a reduced left ventricular function or signs of pulmonary hypertension, was only present in a minority of subjects. CT scans unveiled persisting lung pathologies in 63% of patients, mainly consisting of bilateral ground-glass opacities and/or reticulation in the lower lung lobes, without radiological signs of pulmonary fibrosis. Sequential follow-up evaluations at 60 and 100â days after COVID-19 onset demonstrated a vast improvement of symptoms and CT abnormalities over time. CONCLUSION: A relevant percentage of post-COVID-19 patients presented with persisting symptoms and lung function impairment along with radiological pulmonary abnormalities >100â days after the diagnosis of COVID-19. However, our results indicate a significant improvement in symptoms and cardiopulmonary status over time.
Subject(s)
COVID-19 , Pulmonary Fibrosis , Humans , Lung/diagnostic imaging , Prospective Studies , SARS-CoV-2ABSTRACT
Recombinant erythropoietin (EPO) and iron substitution are a standard of care for treatment of anemias associated with chronic inflammation, including anemia of chronic kidney disease. A black box warning for EPO therapy and concerns about negative side effects related to high-dose iron supplementation as well as the significant proportion of patients becoming EPO resistant over time explains the medical need to define novel strategies to ameliorate anemia of chronic disease (ACD). As hepcidin is central to the iron-restrictive phenotype in ACD, therapeutic approaches targeting hepcidin were recently developed. We herein report the therapeutic effects of a fully human anti-BMP6 antibody (KY1070) either as monotherapy or in combination with Darbepoetin alfa on iron metabolism and anemia resolution in 2 different, well-established, and clinically relevant rodent models of ACD. In addition to counteracting hepcidin-driven iron limitation for erythropoiesis, we found that the combination of KY1070 and recombinant human EPO improved the erythroid response compared with either monotherapy in a qualitative and quantitative manner. Consequently, the combination of KY1070 and Darbepoetin alfa resulted in an EPO-sparing effect. Moreover, we found that suppression of hepcidin via KY1070 modulates ferroportin expression on erythroid precursor cells, thereby lowering potentially toxic-free intracellular iron levels and by accelerating erythroid output as reflected by increased maturation of erythrocyte progenitors. In summary, we conclude that treatment of ACD, as a highly complex disease, becomes more effective by a multifactorial therapeutic approach upon mobilization of endogenous iron deposits and stimulation of erythropoiesis.
Subject(s)
Anemia/therapy , Antibodies, Monoclonal/therapeutic use , Bone Morphogenetic Protein 6/antagonists & inhibitors , Darbepoetin alfa/therapeutic use , Anemia/drug therapy , Anemia/etiology , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/immunology , Arthritis/chemically induced , Arthritis/complications , Bone Marrow/metabolism , Bone Morphogenetic Protein 6/immunology , Cation Transport Proteins/metabolism , Cytokines/blood , Darbepoetin alfa/administration & dosage , Dose-Response Relationship, Drug , Drug Synergism , Erythropoietin/pharmacology , Erythropoietin/therapeutic use , Hep G2 Cells , Humans , Iron/metabolism , Mice , Muscle Proteins/blood , Polysaccharides, Bacterial/toxicity , Random Allocation , Recombinant Proteins/immunology , Renal Insufficiency, Chronic/complicationsABSTRACT
AIMS: Imbalances of iron metabolism have been linked to the development of atherosclerosis. However, subjects with hereditary haemochromatosis have a lower prevalence of cardiovascular disease. The aim of our study was to understand the underlying mechanisms by combining data from genome-wide association study analyses in humans, CRISPR/Cas9 genome editing, and loss-of-function studies in mice. METHODS AND RESULTS: Our analysis of the Global Lipids Genetics Consortium (GLGC) dataset revealed that single nucleotide polymorphisms (SNPs) in the haemochromatosis gene HFE associate with reduced low-density lipoprotein cholesterol (LDL-C) in human plasma. The LDL-C lowering effect could be phenocopied in dyslipidaemic ApoE-/- mice lacking Hfe, which translated into reduced atherosclerosis burden. Mechanistically, we identified HFE as a negative regulator of LDL receptor expression in hepatocytes. Moreover, we uncovered liver-resident Kupffer cells (KCs) as central players in cholesterol homeostasis as they were found to acquire and transfer LDL-derived cholesterol to hepatocytes in an Abca1-dependent fashion, which is controlled by iron availability. CONCLUSION: Our results disentangle novel regulatory interactions between iron metabolism, KC biology and cholesterol homeostasis which are promising targets for treating dyslipidaemia but also provide a mechanistic explanation for reduced cardiovascular morbidity in subjects with haemochromatosis.
Subject(s)
Atherosclerosis , Hemochromatosis Protein , Hemochromatosis , Animals , Atherosclerosis/genetics , Cholesterol, LDL , Clustered Regularly Interspaced Short Palindromic Repeats , Genome-Wide Association Study , Hemochromatosis/genetics , Homeostasis , Humans , Kupffer Cells , Mice , Receptors, LDLABSTRACT
Two distinct forms of the erythropoietin receptor (EPOR) mediate the cellular responses to erythropoietin (EPO) in different tissues. EPOR homodimers signal to promote the maturation of erythroid progenitor cells. In other cell types, including immune cells, EPOR and the ß-common receptor (CD131) form heteromers (the innate repair receptor; IRR), and exert tissue protective effects. We used dextran sulphate sodium (DSS) to induce colitis in C57BL/6 N mice. Once colitis was established, mice were treated with solvent, EPO or the selective IRR agonist cibinetide. We found that both cibinetide and EPO ameliorated the clinical course of experimental colitis in mice, resulting in improved weight gain and survival. Correspondingly, DSS-exposed mice treated with cibinetide or EPO displayed preserved tissue integrity due to reduced infiltration of myeloid cells and diminished production of pro-inflammatory disease mediators including cytokines, chemokines and nitric oxide synthase-2. Experiments using LPS-activated primary macrophages revealed that the anti-inflammatory effects of cibinetide were dependent on CD131 and JAK2 functionality and were mediated via inhibition of NF-κB subunit p65 activity. Cibinetide activation of the IRR exerts potent anti-inflammatory effects, especially within the myeloid population, reduces disease activity and mortality in mice. Cibinetide thus holds promise as novel disease-modifying therapeutic of inflammatory bowel disease.
Subject(s)
Colitis/drug therapy , Colitis/immunology , Disease Progression , Immunity, Innate , Oligopeptides/therapeutic use , Animals , Chemokines/metabolism , Colitis/chemically induced , Colitis/pathology , Cytokine Receptor Common beta Subunit/metabolism , Dextran Sulfate , Erythropoietin/pharmacology , Female , Humans , Immunity, Innate/drug effects , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Janus Kinase 2/metabolism , Macrophages/drug effects , Macrophages/metabolism , Male , Mice, Inbred C57BL , Myeloid Cells/drug effects , Myeloid Cells/metabolism , Oligopeptides/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation/drug effects , Receptors, Erythropoietin/metabolism , Solubility , T-Lymphocytes, Helper-Inducer/drug effects , T-Lymphocytes, Helper-Inducer/metabolism , Transcription Factor RelA/metabolismABSTRACT
Patients with myelofibrosis (MF) often develop anemia and frequently become dependent on red blood cell transfusions. Results from a phase 2 study for the treatment of MF with the Janus kinase 1/2 (JAK1/2) inhibitor momelotinib (MMB) demonstrated that MMB treatment ameliorated anemia, which was unexpected for a JAK1/2 inhibitor, because erythropoietin-mediated JAK2 signaling is essential for erythropoiesis. Using a rat model of anemia of chronic disease, we demonstrated that MMB treatment can normalize hemoglobin and red blood cell numbers. We found that this positive effect is driven by direct inhibition of the bone morphogenic protein receptor kinase activin A receptor, type I (ACVR1), and the subsequent reduction of hepatocyte hepcidin production. Of note, ruxolitinib, a JAK1/2 inhibitor approved for the treatment of MF, had no inhibitory activity on this pathway. Further, we demonstrated the effect of MMB is not mediated by direct inhibition of JAK2-mediated ferroportin (FPN1) degradation, because neither MMB treatment nor myeloid-specific deletion of JAK2 affected FPN1 expression. Our data support the hypothesis that the improvement of inflammatory anemia by MMB results from inhibition of ACVR1-mediated hepcidin expression in the liver, which leads to increased mobilization of sequestered iron from cellular stores and subsequent stimulation of erythropoiesis.
Subject(s)
Anemia/drug therapy , Benzamides/therapeutic use , Bone Morphogenetic Protein Receptors, Type I/antagonists & inhibitors , Hepcidins/biosynthesis , Pyrimidines/therapeutic use , Activin Receptors, Type I/antagonists & inhibitors , Animals , Benzamides/pharmacology , Chronic Disease , Hepatocytes/metabolism , Iron/metabolism , Primary Myelofibrosis/complications , Pyrimidines/pharmacology , RatsABSTRACT
Iron is an essential component of the erythrocyte protein hemoglobin and is crucial to oxygen transport in vertebrates. In the steady state, erythrocyte production is in equilibrium with erythrocyte removal. In various pathophysiological conditions, however, erythrocyte life span is compromised severely, which threatens the organism with anemia and iron toxicity. Here we identify an on-demand mechanism that clears erythrocytes and recycles iron. We show that monocytes that express high levels of lymphocyte antigen 6 complex, locus C1 (LY6C1, also known as Ly-6C) ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate into ferroportin 1 (FPN1, encoded by SLC40A1)-expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1(+)Tim-4(neg) macrophages are transient, reside alongside embryonically derived T cell immunoglobulin and mucin domain containing 4 (Timd4, also known as Tim-4)(high) Kupffer cells (KCs), and depend on the growth factor Csf1 and the transcription factor Nrf2 (encoded by Nfe2l2). The spleen, likewise, recruits iron-loaded Ly-6C(high) monocytes, but these do not differentiate into iron-recycling macrophages, owing to the suppressive action of Csf2. The accumulation of a transient macrophage population in the liver also occurs in mouse models of hemolytic anemia, anemia of inflammation, and sickle cell disease. Inhibition of monocyte recruitment to the liver during stressed erythrocyte delivery leads to kidney and liver damage. These observations identify the liver as the primary organ that supports rapid erythrocyte removal and iron recycling, and uncover a mechanism by which the body adapts to fluctuations in erythrocyte integrity.
Subject(s)
Erythrocytes/metabolism , Hepatocytes/metabolism , Iron/metabolism , Kupffer Cells/metabolism , Liver/metabolism , Anemia , Anemia, Hemolytic , Anemia, Sickle Cell , Animals , Antigens, Ly/metabolism , Cation Transport Proteins/metabolism , Cell Differentiation , Disease Models, Animal , Erythrocytes/cytology , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Inflammation , Kupffer Cells/cytology , Macrophage Colony-Stimulating Factor/metabolism , Macrophages/cytology , Macrophages/metabolism , Membrane Proteins/metabolism , Mice , Monocytes/cytology , Monocytes/metabolism , NF-E2-Related Factor 2/metabolism , SpleenABSTRACT
Lipocalin-2 (Lcn2) is an innate immune peptide with pleiotropic effects. Lcn2 binds iron-laden bacterial siderophores, chemo-attracts neutrophils and has immunomodulatory and apoptosis-regulating effects. In this study, we show that upon infection with Salmonella enterica serovar Typhimurium, Lcn2 promotes iron export from Salmonella-infected macrophages, which reduces cellular iron content and enhances the generation of pro-inflammatory cytokines. Lcn2 represses IL-10 production while augmenting Nos2, TNF-α, and IL-6 expression. Lcn2(-/-) macrophages have elevated IL-10 levels as a consequence of increased iron content. The crucial role of Lcn-2/IL-10 interactions was further demonstrated by the greater ability of Lcn2(-/-) IL-10(-/-) macrophages and mice to control intracellular Salmonella proliferation in comparison to Lcn2(-/-) counterparts. Overexpression of the iron exporter ferroportin-1 in Lcn2(-/-) macrophages represses IL-10 and restores TNF-α and IL-6 production to the levels found in wild-type macrophages, so that killing and clearance of intracellular Salmonella is promoted. Our observations suggest that Lcn2 promotes host resistance to Salmonella Typhimurium infection by binding bacterial siderophores and suppressing IL-10 production, and that both functions are linked to its ability to shuttle iron from macrophages.
Subject(s)
Acute-Phase Proteins/immunology , Homeostasis/immunology , Iron/metabolism , Lipocalins/immunology , Macrophages/metabolism , Oncogene Proteins/immunology , Salmonella Infections, Animal/immunology , Acute-Phase Proteins/metabolism , Animals , Blotting, Western , Lipocalin-2 , Lipocalins/metabolism , Macrophages/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Oncogene Proteins/metabolism , Real-Time Polymerase Chain Reaction , Salmonella Infections, Animal/metabolism , Salmonella typhimurium , TransfectionABSTRACT
Cholesterol metabolism is closely interrelated with cardiovascular disease in humans. Dietary supplementation with omega-6 polyunsaturated fatty acids including arachidonic acid (AA) was shown to favorably affect plasma LDL-C and HDL-C. However, the underlying mechanisms are poorly understood. By combining data from a GWAS screening in >100,000 individuals of European ancestry, mediator lipidomics, and functional validation studies in mice, we identify the AA metabolome as an important regulator of cholesterol homeostasis. Pharmacological modulation of AA metabolism by aspirin induced hepatic generation of leukotrienes (LTs) and lipoxins (LXs), thereby increasing hepatic expression of the bile salt export pump Abcb11. Induction of Abcb11 translated in enhanced reverse cholesterol transport, one key function of HDL. Further characterization of the bioactive AA-derivatives identified LX mimetics to lower plasma LDL-C. Our results define the AA metabolomeasconserved regulator of cholesterol metabolism, and identify AA derivatives as promising therapeutics to treat cardiovascular disease in humans.
Subject(s)
Arachidonic Acid/metabolism , Cholesterol/metabolism , Metabolome , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Arachidonate 5-Lipoxygenase/metabolism , Aspirin/therapeutic use , Atherosclerosis/drug therapy , Atherosclerosis/metabolism , Bile Acids and Salts/metabolism , Cells, Cultured , Cholesterol/blood , Cholesterol, HDL/blood , Cholesterol, HDL/metabolism , Humans , Leukotrienes/metabolism , Liver/drug effects , Liver/metabolism , Mice , Mice, Inbred C57BLABSTRACT
Anemia of chronic disease is a multifactorial disorder, resulting mainly from inflammation-driven reticuloendothelial iron retention, impaired erythropoiesis, and reduced biological activity of erythropoietin. Erythropoiesis-stimulating agents have been used for the treatment of anemia of chronic disease, although with varying response rates and potential adverse effects. Serum concentrations of hepcidin, a key regulator of iron homeostasis, are increased in patients with anemia of chronic disease and linked to the pathogenesis of this disease, because hepcidin blocks cellular iron egress, thus limiting availability of iron for erythropoiesis. We tested whether serum hepcidin levels can predict and affect the therapeutic efficacy of erythropoiesis-stimulating agent treatment using a well-established rat model of anemia of chronic disease. We found that high pre-treatment hepcidin levels correlated with an impaired hematologic response to an erythropoiesis-stimulating agent in rats with anemia of chronic disease. Combined treatment with an erythropoiesis-stimulating agent and an inhibitor of hepcidin expression, LDN-193189, significantly reduced serum hepcidin levels, mobilized iron from tissue stores, increased serum iron levels and improved hemoglobin levels more effectively than did the erythropoiesis-stimulating agent or LDN-193189 monotherapy. In parallel, both the erythropoiesis-stimulating agent and erythropoiesis-stimulating agent/LDN-193189 combined reduced the expression of cytokines known to inhibit erythropoiesis. We conclude that serum hepcidin levels can predict the hematologic responsiveness to erythropoiesis-stimulating agent therapy in anemia of chronic disease. Pharmacological inhibition of hepcidin formation improves the erythropoiesis-stimulating agent's therapeutic efficacy, which may favor a reduction of erythropoiesis-stimulating agent dosages, costs and side effects.