key: cord-0724435-tp8pjj63
authors: Fauter, Maxime; Viel, Sébastien; Zaepfel, Sabine; Pradat, Pierre; Fiscus, Julie; Villard, Marine; Garnier, Lorna; Walzer, Thierry; Sève, Pascal; Henry, Thomas; Jamilloux, Yvan
title: Low glycosylated ferritin is a sensitive biomarker of severe COVID-19
date: 2020-09-11
journal: Cell Mol Immunol
DOI: 10.1038/s41423-020-00544-0
sha: cb45b33282f6b5b07ce8fb9f96441ed0c909c385
doc_id: 724435
cord_uid: tp8pjj63

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Patients with severe COVID-19 had significantly lower levels of lymphocytes and hemoglobin. Leukopenia and thrombopenia, as well as increased levels of PCT, AST, ALT, and ferritin, were significantly more frequent. In these patients, the GF rate was significantly lower (31.6 vs. 41.6%, p = 0.0162).

Patients who succumbed to COVID-19 had significantly less serum hemoglobin, platelets, and lymphocytes. Leukopenia and PCT elevation were also significantly associated with progression to death. The GF rate was not significantly different between dead and live patients (30.1 vs. 38.8%, p = 0.143).

In all these analyses, neither the lymphocyte-to-neutrophil ratio nor the platelet-to-neutrophil ratio was different between groups (data not shown).

We then assessed the ability of certain parameters to serve as biomarkers of disease severity and outcome (Table 1) by constructing ROC curves and calculating the area under the curve (AUC). Among the biomarkers, PCT had the highest AUC for disease severity (AUC = 0.787) and oxygen requirement (AUC = 0.836), whereas lymphocyte count had the highest AUC for death prediction (AUC = 0.861). However, with a cut-off value set at 40%, GF rate had the best sensitivity of all these outcomes (>94%), although it displayed a low specificity (range, 43-55%). Alternatively, the lymphocyte decrease (under 540/mm 3 ) was highly specific (>92%) to severe forms but less sensitive (range, 42-71%). PCT assessment yielded good specificity (>82%) but poor sensitivity (range, 46-56%). Interestingly, for most of these outcomes, assessment of the GF rate was superior to assessment of serum ferritin alone.

Among all these biological parameters, the only correlation observed was between the GF rate and lymphocyte count (r = 0.564, p < 0.0001, Fig. S2 ).

We then assessed the blood levels of a panel of cytokines eventually involved in the COVID-19 immune response 1,2,7 and tested their value as severity biomarkers. Cytokine levels exceeded the upper reference limit in the majority of the patients (62% for IFN-γ, 98% for IL-6, 97% for TNF-α, 63% for IL-18, 82% for MCP-1, 71% for IL-10, and 96% for IL-1Ra and sIL-2R). Except for IL-10, we found no significant differences in cytokines between the groups of patients (Fig. S4) . By analyzing the cytokine profiles, we found that 40% were evocative of macrophage activation (i.e., elevation of at least two cytokines among IL-1Ra, IL-18, or sIL-2R), 13% were marked by IL-6 predominance, 38% were compatible with global hypercytokinemia, and 9% were not specific. Last, we analyzed the kinetics of several parameters in a subset of patients (n = 18) who underwent repeated blood sampling during the disease course (Fig. S2) . Although, due to the limited number of patients, we did not find significant profiles, we observed a trend toward an inverse correlation between GF rate and both IL-6 and IL-10 levels, with values reaching their nadir or maximum between days 7 and 11.

Overall, our results indicate that patients with COVID-19 have heterogeneous cytokine profiles, precluding the use of such profiles as severity or prognosis biomarkers. Conversely, routine biomarkers, such as the PCT or lymphocyte count, had a better specificity than cytokines did but displayed a low sensitivity. The GF rate is a highly sensitive biomarker and better discriminates severe patients than ferritin alone. Thus, the GF rate should be evaluated for its prognostic value in a larger cohort. A combination of the lymphocyte count (<540/mm 3 ), PCT (≥0.5 μg/L), and GF rate (≤40%) could be the basis of a severity score (one point each) that guides clinical decision making. In our cohort, a score ≥ 2 would provide a sensitivity of 71% and a specificity of 95% for disease severity. However, the risk of progression to death remains better evaluated by lymphopenia alone.

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome

COVID-19: consider cytokine storm syndromes and immunosuppression

The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease

Complex immune dysregulation in COVID-19 patients with severe respiratory failure

Secondary HLH is uncommon in severe COVID-19

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Low glycosylated ferritin, a good marker for the diagnosis of hemophagocytic syndrome

Diagnostic value of ferritin and glycosylated ferritin in adult onset Still's disease

The authors would like to thank all the patients, nurses, doctors, residents, and laboratory technicians who took part in the study. The authors are particularly grateful to Nora Martel for assistance with administrative tasks.

The online version of this article (https://doi.org/10.1038/s41423-020-00544-0) contains supplementary material.Competing interests: The authors declare no competing interests.Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.