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Authors: Hippchen, T. et al   

Journal/ Pre-Print:MedRXiv 

Tags: Clinical, Diagnostics, Inflammation 

Research Highlights 

  1. Low serum iron (hypoferraemia) is a common feature of symptomatic SARS-CoV-2 infection 

  1. Serum iron is profoundly low in hospitalised patients requiring high-flow oxygen or mechanical ventilation, and the degree of hypoferraemia could identify patients who required hospitalisation due to COVID-19 more efficiently than other inflammatory indicators - CRP or serum ferritin. 

  1. The iron regulatory hormone hepcidin is raised during SARS-CoV-2, accompanied by perturbations in other indicators of iron status (ferritin, transferrin, transferrin saturation).  

Summary  

This study assesses biomarkers of iron status across three cohorts of varying COVID-19 disease severity: symptomatic, non-hospitalised, outpatients (N=204); hospitalised patients with severe disease (N=81), stratified by oxygen demand; outpatients later hospitalised due to deterioration (N=28).  

All iron biomarkers tested were perturbed in COVID-19 patients. Prominently, serum iron was profoundly low in hospitalised patients, outperforming CRP and ferritin in distinguishing severe disease (inpatients) from outpatients. In a multivariate model, serum iron and ferritin independently associated with being hospitalised (age, sex, CRP adjusted). Hypoferraemia recovery differed between inpatients with high and low oxygen demand. Serum iron was significantly negatively associated with IL-6 throughout. Hepcidin (which causes hypoferraemia) was elevated in inpatients, correlating with IL-6 (known hepcidin agonist); however, there was only weak evidence of association with serum iron, suggesting other factors may contribute to hypoferraemiaThe authors also describe recovery of serum iron following treatment of hospitalised COVID-19 patients with anakinra (IL-1R antagonist), tocilizumab (anti-IL-6R) or immunoglobulin therapy. 

Impact for SARS-CoV2/COVID19 research efforts  

Understand the immune response to SARS-CoV2/COVID19: the paper reports key changes occurring in iron biomarkers in blood in association with the inflammatory response.  

Clinical symptoms and pathogenesis of SARS-Cov2/COVID19: the paper reports strong association of low serum iron with more severe disease; the authors propose that disturbed iron metabolism may play a role in pathophysiology of cardiac and lung injury. 

Develop diagnostic tools for SARS-CoV2/COVID19: potential use of serum iron as an early biochemical indicator of severe disease 

Study Type  

  • Clinical Cohort study (e.g. drug trials) 

Strengths and limitations of the paper 

Novelty:  

  • The largest study to date of iron parameters in COVID-19 patients, including outpatients with milder disease, and associations with IL-6; to our knowledge, this is the first study to report hepcidin in the context of COVID-19. 

Standing in the field: 

  • Hypoferraemia of inflammation is well-described in other infections/inflammatory conditions, but less so in COVID-19 

  • Strong pro-inflammatory responses, prominently including IL-6 induction are well described in COVID-19.  

  • The results of this study are consistent with and extend previous cohort studies that also report marked hypoferraemia and association with disease severity in COVID-19 patients (Shah et al, Crit Care, 2020; Bolondi et al, World J Emerg Surg, 2020; Zhao et al, Open Forum Infectious Diseases, 2020). 

Appropriate statistics: 

  • Statistical analysis of the outpatient cohorts includes multiple datapoints (n=1-8 per individual: n=415 datapoints from n=204 patients in cohort A; n=48 datapoints from n=23 patients in cohort C) from individual patients, yet treats them independently without adjusting for clustering. 

  • Figure 3 uses multiple Mann-Whitney U tests, correcting for multiple testing; the longitudinal nature of the data could be used more efficiently. 

  • No statistical tests were used to investigate differences in Figure 5. 

Viral model used: 

  • [SARS-CoV-2 infected patients] 

Translatability: 

  • Potential for use of serum iron as a cheap, widely available additional measure in assessment of disease severityas also noted by others (see references above). 

Main limitations:  

  • No data on patient co-morbidities, which can frequently influence iron status, is provided. 

  • Lack of justification for ignoring clustering / handling repeated datapoints from the same individuals as independent in analysis of outpatient populations; this could influence the results reported. 

  • In Figure 5, limited numbers of patients were treated with anakinra (IL1R antagonist, n=6) / tocilizumab (anti-IL-6R, n=4) / immunoglobulin (n=6); control groups were not available and there was a lack of clinical/disease severity detail given on the patients: the authors therefore potentially overinterpret these results in attributing the recovery of serum iron to the anti-inflammatory therapies; indeed, the kinetics of serum iron increase appear similar to that presented for low-oxygen demand patients in panel 1 of Figure 3 (many of whom presumably did not receive these therapies).  However, it will be interesting to repeat this analysis from prospective randomised control trials.