The relationship between serum erythropoietin, hepcidin, and haptoglobin levels with disease severity and other biochemical values in patients with COVID‐19

Yağcı, Sema; Serin, Erdinç; Acicbe, Özlem; Zeren, Mustafa İsmet; Odabaşı, Merve Sena

doi:10.1111/ijlh.13479

Cited by 59 publications

(87 citation statements)

References 43 publications

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“…In turn, HIF-1α activation inhibits SARS-CoV-2 infection in the these cells [22], at least in part due to lower ACE2 expression and subsequent reduction of cell attachment of the viral spike protein [29]. In serum, lower levels of EPO have been detected in COVID-19 critical and deceased patient groups than in healthy ones [30].…”

Section: Introductionmentioning

confidence: 99%

Alteration of L-Dopa decarboxylase expression in SARS-CoV-2 infection and its association with the interferon-inducible ACE2 isoform

et al. 2021

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L-Dopa decarboxylase (DDC) is the most significantly co-expressed gene with ACE2, which encodes for the SARS-CoV-2 receptor angiotensin-converting enzyme 2 and the interferon-inducible truncated isoform dACE2. Our group previously showed the importance of DDC in viral infections. We hereby aimed to investigate DDC expression in COVID-19 patients and cultured SARS-CoV-2-infected cells, also in association with ACE2 and dACE2. We concurrently evaluated the expression of the viral infection- and interferon-stimulated gene ISG56 and the immune-modulatory, hypoxia-regulated gene EPO. Viral load and mRNA levels of DDC, ACE2, dACE2, ISG56 and EPO were quantified by RT-qPCR in nasopharyngeal swab samples from COVID-19 patients, showing no or mild symptoms, and from non-infected individuals. Samples from influenza-infected patients were analyzed in comparison. SARS-CoV-2-mediated effects in host gene expression were validated in cultured virus-permissive epithelial cells. We found substantially higher gene expression of DDC in COVID-19 patients (7.6-fold; p = 1.2e-13) but not in influenza-infected ones, compared to non-infected subjects. dACE2 was more elevated (2.9-fold; p = 1.02e-16) than ACE2 (1.7-fold; p = 0.0005) in SARS-CoV-2-infected individuals. ISG56 (2.5-fold; p = 3.01e-6) and EPO (2.6-fold; p = 2.1e-13) were also increased. Detected differences were not attributed to enrichment of specific cell populations in nasopharyngeal tissue. While SARS-CoV-2 virus load was positively associated with ACE2 expression (r≥0.8, p<0.001), it negatively correlated with DDC, dACE2 (r≤−0.7, p<0.001) and EPO (r≤−0.5, p<0.05). Moreover, a statistically significant correlation between DDC and dACE2 expression was observed in nasopharyngeal swab and whole blood samples of both COVID-19 and non-infected individuals (r≥0.7). In VeroE6 cells, SARS-CoV-2 negatively affected DDC, ACE2, dACE2 and EPO mRNA levels, and induced cell death, while ISG56 was enhanced at early hours post-infection. Thus, the regulation of DDC, dACE2 and EPO expression in the SARS-CoV-2-infected nasopharyngeal tissue is possibly related with an orchestrated antiviral response of the infected host as the virus suppresses these genes to favor its propagation.

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Section: Introductionmentioning

confidence: 99%

Alteration of L-Dopa decarboxylase expression in SARS-CoV-2 infection and its association with the interferon-inducible ACE2 isoform

et al. 2021

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“…Decreased serum iron was not completely explained by increased hepcidin in our study, although it correlated with IL-6. The role of hepcidin in the reduction of circulating iron during SARS-CoV-2 infection is controversial [6,12,14]. Our data suggest that other cytokines, such as MCP-1, IL-8 and IL-18 may also modulating iron homeostasis, although the mechanisms are not explored.…”

Section: Discussionmentioning

confidence: 81%

“…Hypoferremia in the context of infection and inflammation is usually attributed to hepcidin [9]. However, contradictory results have been obtained regarding the correlations between iron or hepcidin levels and disease severity [10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

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Iron related biomarkers predict disease severity in a cohort of Portuguese adult patients during COVID-19 acute infection

Moreira

Teles

Silva

et al. 2021

Preprint

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BACKGROUND: Growing evidence indicates a link between iron metabolism and COVID-19 clinical progression, supporting the use of iron and inflammatory parameters as relevant biomarkers to predict patients' outcomes. METHODS: We evaluated iron metabolism and immune response in 303 patients admitted to the main hospital of the northern region of Portugal with variable clinical pictures, from September to November 2020. Of these, 127 tested positive for SARS-CoV-2 and 176 tested negative. Iron-related laboratory parameters and cytokines were determined in blood samples collected soon after admission and, in a subgroup of patients, throughout hospitalization. Demographic data, comorbidities and clinical outcomes were recorded. Patients were assigned into 5 groups according to disease severity. RESULTS: Serum iron and transferrin levels at admission were lower in COVID-19-positive than in COVID-19-negative patients. Conversely, the levels of interleukin(IL)-6 and monocyte chemoattractant protein 1 (MCP1) were increased in COVID-19-positive patients. The lowest serum iron and transferrin levels at diagnosis were associated with the worst outcomes. Iron levels negatively correlated with IL-6 and higher levels of this cytokine were associated with a worse prognosis. Serum ferritin levels at diagnosis were higher in COVID-19-positive than in COVID-19-negative patients but did not correlate with disease severity. Longitudinal determinations of iron and ferritin made in a subgroup of patients (n=23) revealed highly variable results. CONCLUSIONS: Serum iron is the simplest laboratory test to be implemented as a predictor of disease progression in hospitalized acute COVID-19-positive patients. Variation of ferritin with time should be revisited in larger cohorts.

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“…Surprisingly, recent reports showed decreased serum EPO levels in patients with severe COVID-19 (Viruez-Soto et al 2021 ; Yagci et al 2021 ). In the context of hypoxia, as experienced in this condition, we would rather have expected increased levels of EPO as a hypoxia-inducible growth factor (Brines and Cerami 2005 ; Jelkmann 1992 ; Krantz 1991 ).…”

Section: Discussionmentioning

confidence: 97%

Addressing the ‘hypoxia paradox’ in severe COVID-19: literature review and report of four cases treated with erythropoietin analogues

Begemann

Groß

Wincewicz

et al. 2021

Mol Med

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Background Since fall 2019, SARS-CoV-2 spread world-wide, causing a major pandemic with estimated ~ 220 million subjects affected as of September 2021. Severe COVID-19 is associated with multiple organ failure, particularly of lung and kidney, but also grave neuropsychiatric manifestations. Overall mortality reaches > 2%. Vaccine development has thrived in thus far unreached dimensions and will be one prerequisite to terminate the pandemic. Despite intensive research, however, few treatment options for modifying COVID-19 course/outcome have emerged since the pandemic outbreak. Additionally, the substantial threat of serious downstream sequelae, called ‘long COVID’ and ‘neuroCOVID’, becomes increasingly evident. Main body of the abstract Among candidates that were suggested but did not yet receive appropriate funding for clinical trials is recombinant human erythropoietin. Based on accumulating experimental and clinical evidence, erythropoietin is expected to (1) improve respiration/organ function, (2) counteract overshooting inflammation, (3) act sustainably neuroprotective/neuroregenerative. Recent counterintuitive findings of decreased serum erythropoietin levels in severe COVID-19 not only support a relative deficiency of erythropoietin in this condition, which can be therapeutically addressed, but also made us coin the term ‘hypoxia paradox’. As we review here, this paradox is likely due to uncoupling of physiological hypoxia signaling circuits, mediated by detrimental gene products of SARS-CoV-2 or unfavorable host responses, including microRNAs or dysfunctional mitochondria. Substitution of erythropoietin might overcome this ‘hypoxia paradox’ caused by deranged signaling and improve survival/functional status of COVID-19 patients and their long-term outcome. As supporting hints, embedded in this review, we present 4 male patients with severe COVID-19 and unfavorable prognosis, including predicted high lethality, who all profoundly improved upon treatment which included erythropoietin analogues. Short conclusion Substitution of EPO may—among other beneficial EPO effects in severe COVID-19—circumvent downstream consequences of the ‘hypoxia paradox’. A double-blind, placebo-controlled, randomized clinical trial for proof-of-concept is warranted.

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The relationship between serum erythropoietin, hepcidin, and haptoglobin levels with disease severity and other biochemical values in patients with COVID‐19

Cited by 59 publications

References 43 publications

Alteration of L-Dopa decarboxylase expression in SARS-CoV-2 infection and its association with the interferon-inducible ACE2 isoform

Alteration of L-Dopa decarboxylase expression in SARS-CoV-2 infection and its association with the interferon-inducible ACE2 isoform

Iron related biomarkers predict disease severity in a cohort of Portuguese adult patients during COVID-19 acute infection

Addressing the ‘hypoxia paradox’ in severe COVID-19: literature review and report of four cases treated with erythropoietin analogues

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