Association of Hyperferritinemia With Distinct Host Response Aberrations in Patients With Community-Acquired Pneumonia

Xanthe Brands, Tjitske S R van Engelen, Floris M C de Vries, Bastiaan W Haak, Augustijn M Klarenbeek, Maadrika M N P Kanglie, Inge A H van den Berk, Alex R Schuurman, Hessel Peters-Sengers, Natasja A Otto, Daniël R Faber, René Lutter, Brendon P Scicluna, Jaap Stoker, Jan M Prins, W Joost Wiersinga, Tom van der Poll, Xanthe Brands, Tjitske S R van Engelen, Floris M C de Vries, Bastiaan W Haak, Augustijn M Klarenbeek, Maadrika M N P Kanglie, Inge A H van den Berk, Alex R Schuurman, Hessel Peters-Sengers, Natasja A Otto, Daniël R Faber, René Lutter, Brendon P Scicluna, Jaap Stoker, Jan M Prins, W Joost Wiersinga, Tom van der Poll

Abstract

Background: Strongly elevated ferritin levels have been proposed to reflect systemic hyperinflammation in patients admitted to the intensive care unit. Knowledge of the incidence and pathophysiological implications of hyperferritinemia in patients with acute infection admitted to a non-intensive care setting is limited.

Methods: We determined the association between hyperferritinemia, defined by 2 cutoff values (500 and 250 ng/mL), and aberrations in key host response mechanisms among patients with community-acquired pneumonia (CAP) on admission to a general hospital ward (clinicaltrials.gov NCT02928367; trialregister.nl NTR6163).

Results: Plasma ferritin levels were higher in patients with CAP (n = 174; median [interquartile ranges], 259.5 [123.1-518.3] ng/mL) than in age- and sex-matched controls without infection (n = 50; 102.8 [53.5-185.7] ng/mL); P < .001); they were ≥500 ng/mL in 46 patients (26%) and ≥250 ng/mL in 90 (52%). Measurements of 26 biomarkers reflective of distinct pathophysiological domains showed that hyperferritinemia was associated with enhanced systemic inflammation, neutrophil activation, cytokine release, endothelial cell activation and dysfunction, and activation of the coagulation system. Results were robust across different cutoff values.

Conclusions: Hyperferritinemia identifies patients with CAP with a broad deregulation of various host response mechanisms implicated in the pathogenesis of sepsis. This could inform future therapeutic strategies targeting subgroups within the CAP population.

Keywords: biomarker; community-acquired pneumonia; ferritin; host response; immune suppression; sepsis; systemic inflammation.

© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.
Figure 1.
Patients with community-acquired pneumonia (CAP) have higher plasma ferritin levels than controls. Ferritin was measured in plasma samples from patients with CAP at admission (n = 174) and 1 month after admission (n = 88) and from noninfected age- and sex-matched controls (n = 50). Data are expressed as box-and-whisker plots, displaying individual data points and group medians (horizontal solid lines within boxes). Dotted line represents the ferritin cutoff of 500 ng/mL, used for primary analysis (ferritin ≥500 ng/mL, n = 46 patients); dashed line, cutoff of 250 ng/mL, used for secondary analysis (ferritin ≥250 ng/mL, n = 90 patients). Whiskers extend to the farthest point for values that are not outliers (ie, within 1.5 times the lower and upper bounds of the interquartile range). ∗∗∗∗P < .001 for difference between groups.
Figure 2.
Figure 2.
Systemic inflammatory and neutrophil responses in patients with community-acquired pneumonia, stratified according to plasma ferritin concentration (P < .05; ∗∗P < .01; ∗∗∗P < .001 (all Benjamini-Hochberg corrected). Abbreviations: CRP, C-reactive protein; MPO, myeloperoxidase; NGAL, neutrophil gelatinase-associated lipocalin; sCD163, soluble CD163; sTREM, soluble triggering receptor expressed on myeloid cells.
Figure 3.
Figure 3.
Plasma cytokine levels in patients with community-acquired pneumonia stratified according to plasma ferritin concentration (P < .05; ∗∗P < .01; ∗∗∗P < .001 (all Benjamini-Hochberg corrected). Abbreviations: IL-6, IL-8, IL-10, IL-23, IL-27, and IL-1RA, interleukin 6, 8, 10, 23, 27, and 1 receptor antagonist, respectively.
Figure 4.
Figure 4.
Endothelial and coagulant responses of patients with community-acquired pneumonia stratified according to plasma ferritin concentrations (P < .05; ∗∗P < .01 (all Benjamini-Hochberg corrected). Abbreviations: ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; sE-selectin, soluble E-selectin; s-Thrombomodulin, soluble-Thrombomodulin; sTie2, soluble Tie2; sVCAM-1, soluble vascular cell adhesion molecule 1; vWF, von Willebrand factor; TFPI, tissue factor pathway inhibitor.

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Source: PubMed

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