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Cited by 244Iron Metabolism and DisordersCOVID-19 Clinical Research StudiesErythropoietin and Anemia Treatment

Prevalence and Predictive Value of Anemia and Dysregulated Iron Homeostasis in Patients with COVID-19 Infection

Open access
Bellmann-Weiler, Rosa, Lanser, Lukas, Barket, Robert, Rangger, Lukas, Schapfl, Anna, Schaber, Marc, Fritsche, Gernot, Wöll, Ewald +1 more·2020·Journal of Clinical Medicine
DOI 10.3390/jcm9082429PMC PMC7464087
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Abstract

Infections with SARS-CoV-2 can result in severe clinical manifestations. As such patients present with systemic inflammation, we studied the prevalence and predictive value of anemia of inflammation (AI) or functional iron deficiency (FID), originating from immune-mediated alterations of iron homeostasis. Within this retrospective analysis of 259 hospitalized patients with COVID-19, we found that, upon admission, 24.7% were anemic, with the majority suffering from AI (68.8%). Anemia was associated with a significantly higher in-hospital mortality (OR 3.729 (95%CI 1.739–7.995), p = 0.001) but not an increased frequency of intensive care unit (ICU) admission or need for mechanical ventilation. FID was present in 80.0% of patients upon admission, linked to more advanced inflammation and associated with significantly longer hospital stay. Notably, a ferritin/transferrin ratio > 10 predicted a five-fold higher risk of ICU admission and an eight-fold higher risk of the need for mechanical ventilation. Anemia and alterations of iron homeostasis are highly prevalent in hospitalized COVID-19 patients. Iron metabolism biomarkers and hemoglobin can contribute to risk stratification of patients, as initial anemia is associated with increased mortality, whereas alterations of iron homeostasis with a higher ferritin/transferrin ratio reflect more advanced inflammation and predicts subsequent insufficient pulmonary oxygenation with the need for ICU admission and mechanical ventilation.

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Written from the paper’s full text.

TL;DR

In 259 hospitalized patients with PCR-confirmed COVID-19, anemia on admission was present in 24.7% and was associated with higher in-hospital mortality, while functional iron deficiency was very common and linked to more advanced inflammation. A ferritin/transferrin ratio >10 predicted substantially higher risk of ICU admission and mechanical ventilation.

Key findings

  • Among 259 patients, 64 (24.7%) were anemic on admission: mild in 38 (14.7%), moderate in 21 (8.1%), and severe in 5 (1.9%); most anemic patients had anemia of inflammation (68.8%). Anemia was associated with higher in-hospital mortality (OR 3.729, 95%CI 1.739–7.995, p = 0.001; adjusted OR 5.063, 95%CI 1.260–20.345, p = 0.022), but not with ICU admission (OR 0.867, 95%CI 0.424–1.774, p = 0.696) or mechanical ventilation (OR 1.259, 95%CI 0.569–2.788, p = 0.570).
  • Iron metabolism biomarkers were available for 222 patients; 194 (88.2%) had abnormal iron homeostasis, and 176 (79.3%) had functional iron deficiency (FID). FID was associated with poorer clinical condition and longer hospital stay, but not with increased in-hospital death, ICU admission, or mechanical ventilation.
  • A ferritin/transferrin ratio >10 (n = 37) versus ≤10 (n = 185) predicted higher risk of ICU admission (OR 5.702, 95%CI 2.625–12.388, p < 0.001) and need for mechanical ventilation (OR 8.054, 95%CI 3.369–19.249, p < 0.001), and was associated with longer hospital stay (rs = 0.259, p < 0.001).
  • Elevated ferritin was associated with ICU admission (OR 2.780, 95%CI 1.874–4.124, p < 0.001) and mechanical ventilation (OR 3.497, 95%CI 2.124–5.757, p < 0.001); low transferrin was also reported as associated with ICU admission (OR 0.059, 95%CI 0.015–0.226, p < 0.001) and mechanical ventilation (OR 0.079, 95%CI 0.018–0.337, p = 0.001).

Methods

  • Retrospective analysis of 259 patients with PCR-confirmed SARS-CoV-2 infection requiring hospitalization at Innsbruck University Hospital (n = 129) or Hospital St. Vinzenz Zams (n = 130) between 25 February and 20 May 2020.
  • Blood samples were taken at baseline (day 1 ± 1); outcomes recorded included fatal events, ICU admission, and need/duration of invasive ventilation. Anemia was defined by WHO hemoglobin thresholds, and iron status was classified using transferrin saturation and ferritin.
  • Statistical analysis used Shapiro–Wilk, Mann–Whitney U, Kruskal–Wallis, Pearson chi-square, logistic regression, and Spearman rank correlation; p < 0.05 was considered significant.

Limitations

  • The paper states that this was a retrospective observational analysis, so results do not prove causality; iron metabolism variables were not available for all patients, suggesting selection bias and a smaller multivariate sample; hemoglobin as a continuous variable was not significant in multivariate regression, suggesting possible residual confounding for anemia classification; and regional economic/social conditions limit unrestricted generalization.
  • The text also makes evident that the study was conducted in a single region (Tyrol) and that pre-existing anemia was not analyzed as a risk factor for COVID-19 infection or fatal course, which the authors note as a future analysis need.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/jcm9082429

Cites

32 of 32 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 17 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Low transferrin levels upon admission were associated with increased need for mechanical ventilation in hospitalized COVID-19 patients (OR 0.079, 95%CI 0.018-0.337, p=0.001).

    “and the need for mechanical ventilation (OR 0.079 (95%CI 0.018–0.337), p = 0.001, Table S1).”
    Quote in the paperSubstantial claim
  • Findingown data

    Functional iron deficiency was present in approximately 80% of hospitalized COVID-19 patients upon admission.

    “FID was present in 80.0% of patients upon admission”
    • Also stated in: § 3.3. Disturbances of Iron Homeostasis in Patients with COVID-19 Infection · plain
      “the majority of those had functional iron deficiency (FID, n = 176, 79.3%; Table S2).”
    Quote in the paperSubstantial claim
  • Findingown data

    Initial anemia was not associated with increased risk of ICU admission in hospitalized COVID-19 patients (OR 0.867, 95%CI 0.424-1.774, p=0.696).

    “no significant correlations were found between initial anemia and the risk of ICU admission (OR 0.867 (95%CI 0.424−1.774), p = 0.696, Table 3)”
    Quote in the paperSubstantial claim
  • Findingown data

    A ferritin/transferrin ratio >10 was associated with a higher risk of ICU admission compared to a ratio ≤10 in hospitalized COVID-19 patients (OR 5.702, 95%CI 2.625-12.388, p<0.001).

    “A ferritin/transferrin ratio > 10 (n = 37) well discriminated patients with a higher risk of ICU admission (OR 5.702 (95%CI 2.625–12.388), p < 0.001, Figure 1c”
    Quote in the paperSubstantial claim
  • Findingown data

    Ferritin levels positively correlated with CRP, IL-6, and PCT levels in hospitalized COVID-19 patients.

    “ferritin levels positively correlated with CRP (rs = 0.567, p < 0.001), IL-6 (rs = 0.552, p < 0.001) and PCT levels (rs = 0.442, p < 0.001)”
    Quote in the paperSubstantial claim
  • May combine two claims. 16
  • Classified as probably not a substantial claim. 6
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    Functional iron deficiency was not linked to increased risk of in-hospital death, ICU admission, or need for mechanical ventilation in hospitalized COVID-19 patients.

    “but was not linked to an increased risk of in-hospital death, ICU admission or the need for mechanical ventilation (Table 2 and Table 3 and Table S1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No significant relations were found between mortality rate and elevated ferritin levels, low transferrin levels, or low transferrin saturation in hospitalized COVID-19 patients.

    “no significant relations were found between mortality rate and elevated ferritin levels, low Tf levels, or low TfS (Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CRP levels were highly correlated with IL-6 and PCT levels, and IL-6 levels were correlated with PCT levels in hospitalized COVID-19 patients.

    “CRP levels were high significantly correlated to IL-6 levels (rs = 0.757, p < 0.001) and PCT levels (rs = 0.677, p < 0.001), and IL-6 levels also significantly correlated with PCT levels (rs = 0.650, p < 0.001).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Anemic patients had significantly higher CRP, IL-6, and PCT levels than non-anemic patients.

    “anemic patients had significantly higher CRP, IL-6 and PCT levels (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Anemic patients were older, had reduced renal function, and had significantly higher levels of inflammatory markers such as CRP or IL-6.

    “Patients with anemia were older, had a reduced renal function, and had significantly higher levels of inflammatory markers such as CRP or IL-6 (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Serum iron concentration and transferrin, but not transferrin saturation, were significantly lower in anemic subjects whereas ferritin levels were not different.

    “serum iron concentration and transferrin (Tf), but not TfS, were significantly lower in anemic subjects whereas ferritin levels were not different (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Anemia and alterations of iron homeostasis are highly prevalent in hospitalized COVID-19 patients.

    “Anemia and alterations of iron homeostasis are highly prevalent in hospitalized COVID-19 patients.”
    • Also stated in: § 5. Conclusions · plain
      “anemia, and specifically AI, is prevalent in patients with severe COVID-19 disease”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Anemia, and specifically anemia of inflammation, is prevalent in patients with severe COVID-19 disease and is associated with an unfavorable outcome.

    “The results of our study indicate that anemia, and specifically AI, is prevalent in patients with severe COVID-19 disease and is associated with an unfavorable outcome.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    A higher ferritin/transferrin ratio reflects more advanced inflammation and predicts subsequent insufficient pulmonary oxygenation with the need for ICU admission and mechanical ventilation in patients with COVID-19.

    “a ferritin/transferrin ratio > 10 predicted a five-fold higher risk of ICU admission and an eight-fold higher risk of the need for mechanical ventilation.”
    • Also stated in: § 5. Conclusions · plain
      “A higher ferritin/transferrin ratio reflects more advanced inflammation and predicts subsequent insufficient pulmonary oxygenation with the need for ICU admission and mechanical ventilation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Iron metabolism variables were not available for all patients included in the study, depicting a probable selection bias and resulting in a smaller sample size in the multivariate analysis.

    “we did not have iron metabolism variables available for all patients included in the study, depicting a probable selection bias and resulting in a smaller sample size in the multivariate analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Hemoglobin as a continuous variable was not a significant predictor in multivariate regression analysis, depicting the possibility of residual confounding for anemia classification.

    “Hemoglobin as a continuous variable was not a significant predictor in multivariate regression analysis, depicting the possibility of residual confounding for anemia classification.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Premisecitation

    Altered iron homeostasis with more advanced inflammation promotes lung injury and respiratory failure.

    “the latter promoting lung injury and respiratory failure [22,23].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] McGonagle, 2020, The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease, Autoimmun. Rev. source

      Not checked in the free run.

    • cites [23] Channappanavar, 2017, Pathogenic human coronavirus infections: Causes and consequences of cytokine storm and immunopathology, Semin. Immunopathol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Blood samples were analyzed by fully automated tests in the laboratories of the hospitals, which undergo regular quality control.

    “Blood samples were taken from patients at baseline (day 1 ± 1) and were analyzed by fully automated tests in the laboratories of the hospitals, which undergo regular quality control.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    A ferritin/transferrin ratio can discriminate well between true and functional iron deficiency and identify iron deficiency anemia in non-inflammatory subjects with borderline ferritin levels.

    “previous observations indicating that a ferritin/transferrin ratio can discriminate well between true and FID [18] and identify IDA in non-inflammatory subjects with borderline ferritin levels [19]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Theurl, 2006, Dysregulated monocyte iron homeostasis and erythropoietin formation in patients with anemia of chronic disease, Blood source

      Not checked in the free run.

    • cites [19] Castel, 2012, The transferrin/log(ferritin) ratio: A new tool for the diagnosis of iron deficiency anemia, Clin. Chem. Lab. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In COVID-19 patients, elevated ferritin levels were related to disease severity, development of acute respiratory distress syndrome, and death.

    “In COVID-19 patients, elevated ferritin levels were related to disease severity, development of acute respiratory distress syndrome (ARDS) and death [5,7,8].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [5] Zhou, 2020, Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study, Lancet source

      Not checked in the free run.

    • cites [7] Wu, 2020, Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China, JAMA Intern. Med. source

      Not checked in the free run.

    • cites [8] Henry, 2020, Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): A meta-analysis, Clin. Chem. Lab. Med. (CCLM) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inflammation leads to typical alterations of iron homeostasis hallmarked by increased iron acquisition and retention within macrophages along with reduced intestinal iron absorption.

    “Inflammation leads to typical alterations of iron homeostasis hallmarked by increased iron acquisition and retention within macrophages along with reduced intestinal iron absorption [9].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Theurl, 2009, Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: Diagnostic and therapeutic implications, Blood source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The presence of anemia has been linked to an unfavorable clinical course of many diseases, including infections or inflammatory disorders.

    “The presence of anemia has been linked to an unfavorable clinical course of many diseases, including infections or inflammatory disorders [12,13,14,15,16].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [12] Cappellini, 2017, Iron deficiency across chronic inflammatory conditions: International expert opinion on definition, diagnosis, and management, Am. J. Hematol. source

      Not checked in the free run.

    • cites [13] Wouters, 2019, Association of anemia with health-related quality of life and survival: A large population-based cohort study, Haematologica source

      Not checked in the free run.

    • cites [14] Weiss, 2013, Anaemia in inflammatory rheumatic diseases, Nat. Rev. Rheumatol. source

      Not checked in the free run.

    • cites [15] Kurz, 2020, Anaemia, iron status, and gender predict the outcome in patients with chronic heart failure, ESC Heart Fail. source

      Not checked in the free run.

    • cites [16] Wong, M.M.Y., Tu, C., Li, Y., Perlman, R.L., Pecoits-Filho, R., Lopes, A.A., Narita, I., Reichel, H., Port, F.K., and Sukul, N. (2019). Anemia and iron deficiency among chronic kidney disease Stages 3–5ND patients in the Chronic Kidney Disease Outcomes and Practice Patterns Study: Often unmeasured, variably treated. Clin. Kidney J., 1–12. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    As it is in the nature of a retrospective analysis, these results do not prove any causality.

    “As it is in the nature of a retrospective analysis, these results do not prove any causality.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Regional economic/social conditions must be taken into account when interpreting the results, so the findings do not allow unrestricted generalization for all COVID-19 patients.

    “regional economic/social conditions must be taken into account when interpreting the results, which is why the findings do not allow unrestricted generalization for all COVID-19 patients.”
    Quote in the paperNot a substantial claim
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Authors
Bellmann-Weiler, R., Lanser, L., Barket, R., Rangger, L., Schapfl, A., Schaber, M., Fritsche, G., Wöll, E., & Weiss, G.
Affiliations
  • Department of Internal Medicine II, Infectious Disease, Immunology, Rheumatology, Medical University of Innsbruck, 6020 Innsbruck, Austria
  • Innsbruck Medical University (AT)
  • Department of Internal Medicine, St. Vinzenz Krankenhaus Betriebs GmbH, 6511 Zams, Austria
Corresponding author
Weiss, Günter
ORCID
Venue
Journal of Clinical Medicine
Publisher
MDPI AG
Published
2020-07-29
Volume
9
Issue
8
Pages
2429
ISSN
2077-0383 (ISSN-L)
DOI
10.3390/jcm9082429
PMC
PMC7464087
OpenAlex
W3045604366
Cited by
244
References
32
Citations by year
2026: 9 · 2025: 15 · 2024: 33 · 2023: 44 · 2022: 72 · 2021: 58 · 2020: 13
FWCI
29.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Clinical Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Keywords
COVID-19 pandemic, anemia of chronic disease, functional iron deficiency, iron homeostasis, in-hospital mortality, intensive care unit admission, mechanical ventilation, systemic inflammation, risk stratification, hospitalized patients

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