Associations Between Iron Dysregulation, Inflammatory Stress Erythropoiesis And Long-Term COVID-19 Outcomes

COVID-19 News: The global impact of the COVID-19 pandemic extends beyond acute infection, with a growing number of individuals experiencing persistent symptoms, termed post-acute sequelae of Coronavirus Disease 2019 (PASC) or 'long COVID.' This phenomenon, characterized by a spectrum of often nonspecific symptoms, has become a significant healthcare challenge. Despite its prevalence, the drivers of PASC remain unclear. A new study covered in this COVID-19 News report, conducted by the University of Cambridge in the UK sheds light on the potential link between iron dysregulation, inflammatory stress erythropoiesis, and the long-term outcomes of COVID-19.


Transcriptional changes to iron-homeostasis pathway genes in hospitalized patients with COVID-19
a, Distribution of the log2-transformed fold change (FC) values across 324 measured genes with high-quality conserved IREs in their 3′ or 5′ untranslated region derived from the whole-blood transcriptome comparison of COVID-19 severity groups A–E at day 0–14 and HCs. Four genes of interest are annotated. b, Distribution of the log2(FC) across 60 measured genes in the iron-homeostasis gene set at day 0–14 (top) and heat map of gene-level detail for groups A–E versus HCs at day 0–14 (bottom). *P < 0.05, PFDR values from GSEA. c, Schematic of iron-homeostasis pathway (KEGG has04216) with genes colored according to the log2(FC) in group E at day 0–14. Genes corresponding to those shown in the heat map in b are annotated in blue text. d, Polynomial splines showing change in iron-homeostasis scores (PC1 from PCA of iron-homeostasis gene-set genes across all sampling time points for groups A–E). The gray band represents the IQR of the HCs. e, Spearman correlation between iron-homeostasis score and serum iron in groups C–E (scaled residuals following correction for time) at day 0–14, with points colored by severity group.

Thailand Medical News had covered previous studies showing that SARS-CoV-2 is able to bind to hemoglobin and also myoglobin to cause iron dysmetabolism.

https://www.thailandmedical.news/news/covid-19-news-study-validates-that-sars-cov-2-structural-proteins-binds-to-hemoglobin-and-myoglobin-causing-hemoglobin-and-iron-dysmetabolism
 
Understanding PASC
PASC is defined as the unexplained continuation or development of symptoms lasting three months or mor e from the onset of COVID-19. Estimates suggest that up to 30% of individuals infected with SARS-CoV-2 and even 80% of those discharged from hospitals report ongoing symptoms 3-6 months post-infection. Symptoms range from breathing difficulties, fatigue, and muscle weakness to cognitive issues and anxiety/depression. Notably, these persisting symptoms are observed not only in severe cases but also in non-hospitalized individuals.
 
Predictors of PASC
Various factors have been proposed as predictors of PASC, including female sex, increased viral load, lower SARS-CoV-2 antibody titers, longer hospital stays, and reactivation of latent infections. However, the underlying biological and clinical features contributing to prolonged symptoms remain inadequately explored. This study aimed to fill this gap by conducting an extended longitudinal analysis of 214 individuals infected with SARS-CoV-2, examining a range of parameters from immunological and hematological to transcriptomic and clinical data.
 
Immunological Abnormalities and Iron Dysregulation
The study categorized individuals into five groups based on the severity of their COVID-19, ranging from asymptomatic to severe cases requiring assisted ventilation. Notably, immune cell abnormalities persisted beyond the acute phase of the infection, with specific attention to inflammatory anemia and its impact on stress erythropoiesis. Inflammation and disrupted iron homeostasis were observed in hospitalized patients, leading to elevated levels of C-reactive protein (CRP) and various cytokines.
 
Iron Deficiency and Anemia
Hospitalized patients exhibited characteristics of inflammatory anemia, marked by reduced serum iron, low transferrin saturation, and elevated levels of ferritin and hepcidin. Inflammatory anemia is associated with dysregulated iron trafficking and disrupted erythropoiesis in the context of systemic inflammation. The decline in hemoglobin levels and delayed increase in erythropoietin (EPO), a hormone induced by low blood oxygen levels, pointed towards inefficient compensatory stress erythropoiesis.
 
Heme Metabolism Signature
The study identified a distinct heme-metabolism signature in whole-blood transcriptomes of hospitalized patients at 1-3 months post-onset. This coincided with pronounced iron-deficient reticulocytosis, indicating a delayed expansion of heme-producing reticulocytes. Gene expression analysis highlighted upregulation of genes related to heme biosynthesis, reactive oxygen species (ROS), oxidative phosphorylation, and hypoxia pathways, emphasizing the multifaceted impact of iron dysregulation.
 
Iron-Homeostasis Gene Expression
Persistent changes in iron handling were observed, with altered expression of iron-homeostasis genes up to several months after symptom onset. Genes related to both iron overload and iron deprivation were identified, reflecting diverse responses in different blood-cell subsets. These shifts in transcriptional response correlated with inflammatory parameters and inversely correlated with serum iron levels.
 
Single-Cell Analysis
Single-cell analysis revealed preferential expression of iron-homeostasis genes in monocytes, indicating their role in iron sequestration and potential contribution to iron deprivation in proliferating lymphocytes. Iron-laden macrophages were identified, aligning with the observed iron accumulation in post-mortem samples from fatal COVID-19 cases.
 
Linking Acute Severity to PASC
The study emphasized the association between unresolved inflammation, iron dysregulation, and the risk of developing PASC. Serum iron levels and transferrin saturation were significantly lower, and inflammatory markers remained elevated in individuals reporting PASC compared to those without persisting symptoms, even when adjusting for age, sex, and acute disease severity.
 
Implications for Long-Term Health
The findings suggest that disruptions to iron homeostasis, dysregulated erythropoiesis, and immune dysfunction contribute to inefficient oxygen transport, inflammatory disequilibrium, and persisting symptoms in COVID-19 survivors. Notably, the impact of inflammatory iron dysregulation on long-term erythropoiesis and oxygen carriage may drive PASC, influencing strategies for prevention and treatment.
 
Therapeutic Strategies
The study proposes potential therapeutic strategies, including iron supplementation, hepcidin inhibitors, and IL-6 inhibition, to mitigate the impact of early iron dysregulation on both acute COVID-19 severity and the development of PASC. The observed protective effect of increased iron availability in individuals with β-thalassemia and preliminary reports on iron treatment in COVID-19 patients support the exploration of these interventions.
 
Conclusion
In summary, the University of Cambridge's comprehensive study provides valuable insights into the link between iron dysregulation, inflammatory stress erythropoiesis, and the long-term outcomes of COVID-19. Understanding these underlying mechanisms may pave the way for targeted therapeutic approaches and preventive strategies to alleviate the burden of PASC and improve the overall health outcomes of COVID-19 survivors.
 
The study findings were published in the peer reviewed journal: Nature Immunology.
https://www.nature.com/articles/s41590-024-01754-8
 
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