Normoferremia in Patients with Acute Bacterial Infections—A Hitherto Unexplored Field of the Dichotomy between CRP and Ferritin Expression in Patients with Hyper Inflammation and Failure to Increase Ferritin
Abstract
1. Introduction
2. Results
3. Materials and Methods
3.1. The Patients
3.2. Laboratory Methods
3.3. Statistical Methods
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Kernan, K.; Carcillo, J.A. Hyperferritinemia and Inflammation. Int. Immunol. 2017, 29, 401–409. [Google Scholar] [CrossRef] [PubMed]
- Slaats, J.; ten Oever, J.; van de Veerdonk, F.L.; Netea, M.G. IL-1β/IL-6/CRP and IL-18/Ferritin: Distinct Inflammatory Programs in Infections. PLoS Pathog. 2016, 12, e1005973. [Google Scholar] [CrossRef] [PubMed]
- Muckenthaler, M.U.; Rivella, S.; Hentze, M.W.; Galy, B. A Red Carpet for Iron Metabolism. Cell 2017, 168, 344–361. [Google Scholar] [CrossRef] [PubMed]
- Weinberg, E.D. Iron Withholding: A Defense against Infection and Neoplasia. Physiol. Rev. 1984, 64, 65–102. [Google Scholar] [CrossRef]
- Carrondo, M.A. Ferritins, Iron Uptake and Storage from the Bacterioferritin Viewpoint. EMBO J. 2003, 22, 1959–1968. [Google Scholar] [CrossRef]
- Arosio, P.; Adelman, T.G.; Drysdale, J.W. On Ferritin Heterogeneity. Further Evidence for Heteropolymers. J. Biol. Chem. 1978, 253, 4451–4458. [Google Scholar] [CrossRef]
- Arosio, P.; Levi, S. Ferritin, Iron Homeostasis, and Oxidative Damage. Free Radic. Biol. Med. 2002, 33, 457–463. [Google Scholar] [CrossRef]
- Yamashita, M.; Harada, G.; Matsumoto, S.; Aiba, Y.; Ichikawa, A.; Fujiki, T.; Udono, M.; Kabayama, S.; Yoshida, T.; Zhang, P.; et al. Suppression of Immunoglobulin Production in Human Peripheral Blood Mononuclear Cells by Monocytes via Secretion of Heavy-Chain Ferritin. Immunobiology 2014, 219, 149–157. [Google Scholar] [CrossRef]
- Gray, C.P.; Arosio, P.; Mersey, P. Heavy Chain Ferritin Activates Regulatory T Cells by Induction of Changes in Dendritic Cells. Blood 2002, 99, 3326–3334. [Google Scholar] [CrossRef]
- Zarjou, A.; Black, L.M.; McCullough, K.R.; Hull, T.D.; Esman, S.K.; Boddu, R.; Varambally, S.; Chandrashekar, D.S.; Feng, W.; Arosio, P.; et al. Ferritin Light Chain Confers Protection against Sepsis-Induced Inflammation and Organ Injury. Front. Immunol. 2019, 10, 131. [Google Scholar] [CrossRef]
- Haschka, D.; Tymoszuk, P.; Petzer, V.; Hilbe, R.; Heeke, S.; Dichtl, S.; Skvortsov, S.; Demetz, E.; Berger, S.; Seifert, M.; et al. Ferritin H Deficiency Deteriorates Cellular Iron Handling and Worsens Salmonella Typhimurium Infection by Triggering Hyperinflammation. JCI Insight 2021, 6, e141760. [Google Scholar] [CrossRef] [PubMed]
- Nemeth, E.; Tuttle, M.S.; Powelson, J.; Vaughn, M.D.; Donovan, A.; Ward, D.M.V.; Ganz, T.; Kaplan, J. Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization. Science 2004, 306, 2090–2093. [Google Scholar] [CrossRef]
- Al Jaberi, S.; Cohen, A.; D’Souza, C.; Abdulrazzaq, Y.M.; Ojha, S.; Bastaki, S.; Adeghate, E.A. Lipocalin-2: Structure, Function, Distribution and Role in Metabolic Disorders. Biomed. Pharmacother. 2021, 142, 112002. [Google Scholar] [CrossRef] [PubMed]
- Miethke, M.; Marahiel, M.A. Siderophore-Based Iron Acquisition and Pathogen Control. Microbiol. Mol. Biol. Rev. 2007, 71, 413–451. [Google Scholar] [CrossRef] [PubMed]
- De Matteis, A.; Colucci, M.; Rossi, M.N.; Caiello, I.; Merli, P.; Tumino, N.; Bertaina, V.; Pardeo, M.; Bracaglia, C.; Locatelli, F.; et al. Expansion of CD4dimCD8+ T Cells Characterizes Macrophage Activation Syndrome and Other Secondary HLH. Blood 2022, 140, 262–273. [Google Scholar] [CrossRef]
- Hoppe, M.; Lonnerdal, B.; Hossain, M.B.; Olsson, S.; Lönnerdal, B.; Hossain, B.; Nilsson, F.; Lundberg, P.-A.; Rödjer, S.; Hulthén, L. Hepcidin, Interleukin-6 and Hematological Iron Markers in Males before and after Heart Surgery. J. Nutr. Biochem. 2009, 20, 11–16. [Google Scholar] [CrossRef]
- Elin, R.; Wolff, S.; Finch, C. Effect of Induced Fever on Serum Iron and Ferritin Concentrations in Man. Blood 1977, 49, 147–153. [Google Scholar] [CrossRef]
- Birgegård, G.; Hällgren, R.; Killander, A.; Venge, P.; Wide, L. Serum Ferritin During Infection. Acta Med. Scand. 1979, 205, 641–645. [Google Scholar] [CrossRef]
- Karschnia, P.; Jordan, J.T.; Forst, D.A.; Arrillaga-Romany, I.C.; Batchelor, T.T.; Baehring, J.M.; Clement, N.F.; Nicolas Gonzalez Castro, L.; Herlopian, A.; Maus, M.V.; et al. Clinical Presentation, Management, and Biomarkers of Neurotoxicity after Adoptive Immunotherapy with CAR T Cells. Blood 2019, 133, 2212–2221. [Google Scholar] [CrossRef]
- Fauter, M.; Mainbourg, S.; El Jammal, T.; Guerber, A.; Zaepfel, S.; Henry, T.; Gerfaud-Valentin, M.; Sève, P.; Jamilloux, Y. Extreme Hyperferritinemia: Causes and Prognosis. J. Clin. Med. 2022, 11, 5438. [Google Scholar] [CrossRef]
- Kossiva, L.; Gourgiotis, D.I.; Tsentidis, C.; Anastasiou, T.; Marmarinos, A.; Vasilenko, H.; Sdogou, T.; Georgouli, H. Serum Hepcidin and Ferritin to Iron Ratio in Evaluation of Bacterial versus Viral Infections in Children: A Single-Center Study. Pediatr. Infect. Dis. J. 2012, 31, 795–798. [Google Scholar] [CrossRef] [PubMed]
- Xu, T.; Wang, L.; Wu, S.; Zhou, F.; Huang, H. Utility of a Simple Scoring System in Differentiating Bacterial Infections in Cases of Fever of Unknown Origin. Clin. Infect. Dis. 2020, 71 (Suppl. S4), S409–S415. [Google Scholar] [CrossRef] [PubMed]
- Weinberg, E.D. Nutritional Immunity: Host’s Attempt to Withhold Iron from Microbial Invaders. JAMA 1975, 231, 39–41. [Google Scholar] [CrossRef]
- Esan, M.O.; Van Hensbroek, M.B.; Nkhoma, E.; Musicha, C.; White, S.A.; Ter Kuile, F.O.; Phiri, K.S. Iron Supplementation in HIV-Infected Malawian Children with Anemia: A Double-Blind, Randomized, Controlled Trial. Clin. Infect. Dis. 2013, 57, 1626–1634. [Google Scholar] [CrossRef] [PubMed]
- Zimmermann, M.; Chassard, C.; Rohner, F.; N’goran, E.K.; Nindjin, C.; Dostal, A.; Utzinger, J.; Ghattas, H.; Lacroix, C.; Hurrell, R.F.; et al. The Effects of Iron Fortification on the Gut Microbiota in African Children: A Randomized Controlled Trial in Cote d’Ivoire. Am. J. Clin. Nutr. 2010, 92, 1406–1415. [Google Scholar] [CrossRef] [PubMed]
- Soofi, S.; Cousens, S.; Iqbal, S.P.; Akhund, T.; Khan, J.; Ahmed, I.; Zaidi, A.K.M.; Bhutta, Z.A. Effect of Provision of Daily Zinc and Iron with Several Micronutrients on Growth and Morbidity among Young Children in Pakistan: A Cluster-Randomised Trial. Lancet 2013, 382, 29–40. [Google Scholar] [CrossRef]
- Malan, L.; Baumgartner, J.; Calder, P.C.; Zimmermann, M.B.; Smuts, C.M. N–3 Long-Chain PUFAs Reduce Respiratory Morbidity Caused by Iron Supplementation in Iron-Deficient South African Schoolchildren: A Randomized, Double-Blind, Placebo-Controlled Intervention. Am. J. Clin. Nutr. 2015, 101, 668–679. [Google Scholar] [CrossRef]
- Sazawal, S.; Black, R.; Ramsan, M.; Lancet, H.C.-T.; Chwaya, H.M.; Stoltzfus, R.J.; Dutta, A.; Dhingra, U.; Kabole, I.; Deb, S.; et al. Effects of Routine Prophylactic Supplementation with Iron and Folic Acid on Admission to Hospital and Mortality in Preschool Children in a High Malaria Transmission Setting: Community-Based, Randomised, Placebo-Controlled Trial. Lancet 2006, 367, 133–143. [Google Scholar] [CrossRef]
- Marques, O.; Weiss, G.; Muckenthaler, M.U. The Role of Iron in Chronic Inflammatory Diseases: From Mechanisms to Treatment Options in Anemia of Inflammation. Blood 2022, 140, 2011–2023. [Google Scholar] [CrossRef]
- Shah, A.; Donovan, K.; Seeley, C.; Dickson, E.A.; Palmer, A.J.R.; Doree, C.; Brunskill, S.; Reid, J.; Acheson, A.G.; Sugavanam, A.; et al. Risk of Infection Associated with Administration of Intravenous Iron: A Systematic Review and Meta-Analysis. JAMA Netw. Open. 2021, 4, e2133935. [Google Scholar] [CrossRef]
- Ganz, T. Iron and Infection. Int. J. Hematol. 2018, 107, 7–15. [Google Scholar] [CrossRef] [PubMed]
- Griffiths, E. Iron and Bacterial Virulence—A Brief Overview. Biol. Met. 1991, 4, 7–13. [Google Scholar] [CrossRef] [PubMed]
- Muhsen, K.; Barak, M.; Shifnaidel, L.; Nir, A.; Bassal, R.; Cohen, D. Helicobacter Pylori Infection Is Associated with Low Serum Ferritin Levels in Israeli Arab Children-A Seroepidemiologic Study. J. Pediatr. Gastroenterol. Nutr. 2009, 49, 262–264. [Google Scholar] [CrossRef] [PubMed]
- Gessner, B.D.; Baggett, H.C.; Muth, P.T.; Dunaway, E.; Gold, B.D.; Feng, Z.; Parkinson, A.J. A Controlled, Household-Randomized, Open-Label Trial of the Effect That Treatment of Helicobacter Pylori Infection Has on Iron Deficiency in Children in Rural Alaska. J. Infect. Dis. 2006, 193, 537–546. [Google Scholar] [CrossRef] [PubMed]
- Pandey, R.; Rodriguez, G.M. A Ferritin Mutant of Mycobacterium Tuberculosis Is Highly Susceptible to Killing by Antibiotics and Is Unable to Establish a Chronic Infection in Mice. Infect. Immun. 2012, 80, 3650–3659. [Google Scholar] [CrossRef]
- Hor, L.I.; Chang, T.T.; Wang, S.T. Survival of Vibrio Vulnificus in Whole Blood from Patients with Chronic Liver Diseases: Association with Phagocytosis by Neutrophils and Serum Ferritin Levels. J. Infect. Dis. 1999, 179, 275–278. [Google Scholar] [CrossRef]
- Larson, J.A.; Howie, H.L.; So, M. Neisseria Meningitidis Accelerates Ferritin Degradation in Host Epithelial Cells to Yield an Essential Iron Source. Mol. Microbiol. 2004, 53, 807–820. [Google Scholar] [CrossRef]
- Dehner, C.; Morales-Soto, N.; Behera, R.K.; Shrout, J.; Theil, E.C.; Maurice, P.A.; Dubois, J.L. Ferritin and Ferrihydrite Nanoparticles as Iron Sources for Pseudomonas Aeruginosa. J. Biol. Inorg. Chem. 2013, 18, 371–381. [Google Scholar] [CrossRef]
- Whitby, P.W.; Vanwagoner, T.M.; Springer, J.M.; Morton, D.J.; Seale, T.W.; Stull, T.L. Burkholderia Cenocepacia Utilizes Ferritin as an Iron Source. J. Med Microbiol. 2006, 55, 661–668. [Google Scholar] [CrossRef]
- Bauckman, K.A.; Mysorekar, I.U. Ferritinophagy Drives Uropathogenic Escherichia Coli Persistence in Bladder Epithelial Cells. Autophagy 2016, 12, 850–863. [Google Scholar] [CrossRef]
- Segond, D.; Abi Khalil, E.; Buisson, C.; Daou, N.; Kallassy, M.; Lereclus, D.; Arosio, P.; Bou-Abdallah, F.; Nielsen Le Roux, C. Iron Acquisition in Bacillus Cereus: The Roles of IlsA and Bacillibactin in Exogenous Ferritin Iron Mobilization. PLOS Pathog. 2014, 10, e1003935. [Google Scholar] [CrossRef] [PubMed]
- Deneer, H.G.; Healey, V.; Boychuk, I. Reduction of Exogenous Ferric Iron by a Surface-Associated Ferric Reductase of Listeria spp. Microbiology 1995, 141 Pt 8, 1985–1992. [Google Scholar] [CrossRef] [PubMed]
- Nicolle, L.E. Urinary tract infection in the elderly. How to treat and when? Infection 1992, 20 (Suppl. S4), s261–s265. [Google Scholar] [CrossRef] [PubMed]
- Cheng, L.; Li, H.; Li, L.; Liu, C.; Yan, S.; Chen, H.; Li, Y. Ferritin in the corona virus disease 2019 (COVID-19): A systemic review and meta-analysis. J. Clin. Lab. Anal. 2020, 34, e23618. [Google Scholar] [CrossRef]
- Sack, G.H. Serum Amyloid A—A Review. Mol. Med. 2018, 24, 46. [Google Scholar] [CrossRef]
Infectious Syndrome | No. of Patients (%) |
---|---|
Pneumonia | 75 (38.46) |
UTI | 60 (30.77) |
Skin infection | 22 (11.28) |
URTI | 7 (3.59) |
GI infection | 7 (3.59) |
COVID-19 | 7 (3.59) |
Sepsis of unknown source | 6 (3.08) |
Nervous system infection | 3 (1.54) |
Other | 8 (4.1) |
Infectious Agent | No. of Cases (%) | |
---|---|---|
Bacteria | E. coli | 41 (46.07) |
Streptococcal species | 7 (7.87) | |
Haemophilus influenzae | 6 (6.74) | |
Klebsiella pneumoniae | 4 (4.49) | |
Proteus mirabilis | 3 (3.37) | |
Pseudomonas aeruginosa | 3 (3.37) | |
Enterococcal species | 2 (2.24) | |
Other | 9 (10.11) | |
Virus | SARS-CoV-2 | 5 (5.62) |
Influenza A | 1 (1.12) | |
Mixed infection | 8 (8.99) |
Time (h) | <24 | 24–48 | 48–72 | 72–96 | >96 | Total | p Value | |
---|---|---|---|---|---|---|---|---|
N = 28 | N = 49 | N = 40 | N = 43 | N = 65 | N = 225 | |||
Sex | Male | 11.0 | 13.0 | 7.0 | 8.0 | 15.0 | 54.0 | 0.248 |
Female | 17.0 | 36.0 | 33.0 | 35.0 | 50.0 | 171.0 | ||
Age (years) | 73 (63.3–83.5) | 73.3 (53.3–83.6) | 76.6 (56.6–84.6) | 74.9 (53.7–83.8) | 66.1 (40.4–82.2) | 73.3 (52.9–83.4) | 0.161 | |
Hemoglobin (g/dL) | 10.1 (9.3–12.2) | 10.2 (9.3–11.4) | 10 (8.9–10.9) | 10.1 (9.55–11.25) | 9.7 (9–11.6) | 10 (9.1–11.4) | 0.744 | |
Iron (mcg/dL) | 9 (7–12.5) | 8 (6–10.7) | 8 (6.95–12) | 10 (8.25–14) | 11 (8–15.5) | 10 (7–13) | 0.671 | |
Transferrin (mg/dL) | 216 (181–226) | 190 (152–214) | 215 (184–250) | 193 (169 –203) | 196 (175–225) | 196 (171 – 225) | 0.247 | |
Transferrin saturation (%) | 3.2 (2–3.9) | 3.2 (2.6–4.7) | 2.8 (2.2–3.9) | 4 (2.8–5.5) | 4.1 (2.7–6.2) | 3.3 (2.5–5.2) | 0.669 | |
Ferritin (ng/mL) | 87.3 (7.3–122.9) | 106.6 (86.9–135) | 97.9 (83.4–128.9) | 120 (97.5–141) | 110.4 (86.8–133.7) | 109.9 (85.1–131.7) | 0.51 | |
CRP (mg/L) | 230.7 (218.7–268.7) | 248.4 (215.5–301.1) | 254.6 (223.4–276) | 255.8 (240.6–285.9) | 255.8 (240.6–285.9) | 248.4 (221–277.5) | 0.688 | |
Type | Infectious | 24 | 45 | 35 | 39 | 52 | 195 | 0.032 |
Non-infectious | 4 | 2 | 4 | 4 | 4 | 18 | ||
Undetermined | 0 | 2 | 1 | 0 | 9 | 12 |
≤24 h | 24.1–48 h | 48.1–72 h | 72.1–96 h | >96 h | Total | |
---|---|---|---|---|---|---|
Infectious | 24 | 45 | 35 | 39 | 52 | 195 |
Non-infectious | 4 | 2 | 4 | 4 | 4 | 18 |
Undetermined | 0 | 2 | 1 | 0 | 9 | 12 |
Total | 28 | 49 | 40 | 43 | 65 | 225 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Levinson, T.; Feigin, E.; Berliner, S.; Shenhar-Tsarfaty, S.; Shapira, I.; Rogowski, O.; Zeltzer, D.; Goldiner, I.; Shtark, M.; Katz Shalhav, M.; et al. Normoferremia in Patients with Acute Bacterial Infections—A Hitherto Unexplored Field of the Dichotomy between CRP and Ferritin Expression in Patients with Hyper Inflammation and Failure to Increase Ferritin. Int. J. Mol. Sci. 2023, 24, 11350. https://doi.org/10.3390/ijms241411350
Levinson T, Feigin E, Berliner S, Shenhar-Tsarfaty S, Shapira I, Rogowski O, Zeltzer D, Goldiner I, Shtark M, Katz Shalhav M, et al. Normoferremia in Patients with Acute Bacterial Infections—A Hitherto Unexplored Field of the Dichotomy between CRP and Ferritin Expression in Patients with Hyper Inflammation and Failure to Increase Ferritin. International Journal of Molecular Sciences. 2023; 24(14):11350. https://doi.org/10.3390/ijms241411350
Chicago/Turabian StyleLevinson, Tal, Eugene Feigin, Shlomo Berliner, Shani Shenhar-Tsarfaty, Itzhak Shapira, Ori Rogowski, David Zeltzer, Ilana Goldiner, Moshe Shtark, Malka Katz Shalhav, and et al. 2023. "Normoferremia in Patients with Acute Bacterial Infections—A Hitherto Unexplored Field of the Dichotomy between CRP and Ferritin Expression in Patients with Hyper Inflammation and Failure to Increase Ferritin" International Journal of Molecular Sciences 24, no. 14: 11350. https://doi.org/10.3390/ijms241411350
APA StyleLevinson, T., Feigin, E., Berliner, S., Shenhar-Tsarfaty, S., Shapira, I., Rogowski, O., Zeltzer, D., Goldiner, I., Shtark, M., Katz Shalhav, M., & Wasserman, A. (2023). Normoferremia in Patients with Acute Bacterial Infections—A Hitherto Unexplored Field of the Dichotomy between CRP and Ferritin Expression in Patients with Hyper Inflammation and Failure to Increase Ferritin. International Journal of Molecular Sciences, 24(14), 11350. https://doi.org/10.3390/ijms241411350