{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T19:45:41Z","timestamp":1792093541578,"version":"4.4.0"},"reference-count":45,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T00:00:00Z","timestamp":1643846400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Acibadem Labmed Clinical Laboratories"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Background<\/jats:title><jats:p>Coronavirus disease (COVID-19) has a severe impact on all aspects of patient care. Among the numerous biomarkers of potential validity for diagnostic and clinical management of COVID-19 are biomarkers at the interface of iron metabolism and inflammation.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Methods<\/jats:title><jats:p>The follow-up study included 54 hospitalized patients with laboratory-confirmed COVID-19 with a moderate and severe\/critical form of the disease. Iron deficiency specific biomarkers such as iron, ferritin, transferrin receptor, hepcidin, and zinc protoporphyrin (ZnPP) as well as relevant markers of inflammation were evaluated twice: in the first five days when the patient was admitted to the hospital and during five to 15 days; and their validity to diagnose iron deficiency was further assessed. The regression and Receiver Operating Characteristics (ROC) analyses were performed to evaluate the prognosis and determine the probability for predicting the severity of the disease in the first five days of COVID-19.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Results<\/jats:title><jats:p>Based on hemoglobin values, anemia was observed in 21 of 54 patients. Of all iron deficiency anemia-related markers, only ZnPP was significantly elevated (P&lt;0.001) in the anemic group. When patients were grouped according to the severity of disease, slight differences in hemoglobin or other anemia-related parameters could be observed. However, the levels of ZnPP were significantly increased in the severely ill group of patients. The ratio of ZnPP to lymphocyte count (ZnPP\/L) had a discrimination power stronger than the neutrophil to lymphocyte count ratio (N\/L) to determine disease severity. Additionally, only two markers were independently associated with the severity of COVID-19 in logistic regression analysis; D-dimer (OR (5.606)(95% CI 1.019\u201330.867)) and ZnPP\/L ratio (OR (74.313) (95% CI 1.081\u20135108.103)).<\/jats:p><\/jats:sec><jats:sec id=\"sec004\"><jats:title>Conclusions<\/jats:title><jats:p>For the first time ZnPP in COVID-19 patients were reported in this study. Among all iron-related markers tested, ZnPP was the only one that was associated with anemia as based on hemoglobin. The increase in ZnPP might indicate that the underlying cause of anemia in COVID-19 patients is not only due to the inflammation but also of nutritional origin. Additionally, the ZnPP\/L ratio might be a valid prognostic marker for the severity of COVID-19.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pone.0262487","type":"journal-article","created":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T18:55:24Z","timestamp":1643914524000},"page":"e0262487","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":18,"title":["Zinc protoporphyrin levels in COVID-19 are indicative of iron deficiency and potential predictor of disease severity"],"prefix":"10.1371","volume":"17","author":[{"given":"Meltem","family":"Kilercik","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasemin","family":"Ucal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhittin","family":"Serdar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Serteser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7399-4929","authenticated-orcid":true,"given":"Aysel","family":"Ozpinar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian J.","family":"Schweigert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,2,3]]},"reference":[{"key":"pone.0262487.ref001","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1592\/phco.28.10.1267","article-title":"Anemia of critical illness","volume":"28","author":"K. Asare","year":"2008","journal-title":"Pharmacotherapy"},{"key":"pone.0262487.ref002","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.ccc.2012.04.012","article-title":"Anemia in the ICU: anemia of chronic disease versus anemia of acute illness","volume":"28","author":"D. Prakash","year":"2012","journal-title":"Crit Care Clin"},{"key":"pone.0262487.ref003","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1016\/S0140-6736(98)00088-9","article-title":"Unrecognised iron deficiency in critical illness","author":"MC Bellamy","year":"1998","journal-title":"Lancet (London, England). England"},{"key":"pone.0262487.ref004","doi-asserted-by":"crossref","first-page":"3462","DOI":"10.1016\/j.clnu.2020.11.033","article-title":"Association between iron status and the risk of adverse outcomes in COVID-19","volume":"40","author":"Y Lv","year":"2021","journal-title":"Clin Nutr"},{"key":"pone.0262487.ref005","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1002\/jmv.26444","article-title":"Anemia is associated with severe illness in COVID-19: A retrospective cohort study","volume":"93","author":"Z Tao","year":"2021","journal-title":"J Med Virol"},{"key":"pone.0262487.ref006","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1515\/cclm-2020-0369","article-title":"Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis","volume":"58","author":"BM Henry","year":"2020","journal-title":"Clin Chem Lab Med"},{"key":"pone.0262487.ref007","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1177\/0310057X0102900504","article-title":"Functional iron deficiency, infection and systemic inflammatory response syndrome in critical illness","volume":"29","author":"MV Patteril","year":"2001","journal-title":"Anaesth Intensive Care"},{"key":"pone.0262487.ref008","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1097\/TA.0000000000002147","article-title":"Persistent inflammation and anemia among critically ill septic patients","volume":"86","author":"TJ Loftus","year":"2019","journal-title":"J Trauma Acute Care Surg"},{"key":"pone.0262487.ref009","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s10741-008-9086-x","article-title":"Iron and anemia in human biology: a review of mechanisms","volume":"13","author":"GJ Handelman","year":"2008","journal-title":"Heart Fail Rev"},{"key":"pone.0262487.ref010","first-page":"14","article-title":"Anemia of chronic disease: pathophysiology and laboratory diagnosis","volume":"11","author":"C Thomas","year":"2005","journal-title":"Lab Hematol Off Publ Int Soc Lab Hematol"},{"key":"pone.0262487.ref011","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1177\/0004563216675185","article-title":"Ferritin and iron studies in anaemia and chronic disease","volume":"54","author":"YY Peng","year":"2017","journal-title":"Ann Clin Biochem"},{"key":"pone.0262487.ref012","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1097\/ALN.0b013e3182065c57","article-title":"Hepcidin and anemia of the critically ill patient: bench to bedside","volume":"114","author":"S Lasocki","year":"2011","journal-title":"Anesthesiology"},{"key":"pone.0262487.ref013","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1111\/bjh.12311","article-title":"Guideline for the laboratory diagnosis of functional iron deficiency","volume":"161","author":"DW Thomas","year":"2013","journal-title":"Br J Haematol"},{"key":"pone.0262487.ref014","article-title":"Zinc Protoporphyrin Is a Reliable Marker of Functional Iron Deficiency in Patients with Inflammatory Bowel Disease","volume":"11","author":"E Leventi","year":"2021","journal-title":"Diagnostics (Basel, Switzerland)"},{"key":"pone.0262487.ref015","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1007\/s10654-020-00678-5","article-title":"Anemia and iron metabolism in COVID-19: a systematic review and meta-analysis","volume":"35","author":"PE Taneri","year":"2020","journal-title":"Eur J Epidemiol"},{"key":"pone.0262487.ref016","doi-asserted-by":"crossref","first-page":"3996","DOI":"10.1021\/acschemneuro.0c00572","article-title":"COVID-19 and Body Iron: A Survey on Phenomenological and Genetic Correlations","volume":"11","author":"R. Lawaczeck","year":"2020","journal-title":"ACS Chem Neurosci"},{"key":"pone.0262487.ref017","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1093\/clinchem\/27.2.220","article-title":"Simultaneous quantitation of zinc protoporphyrin and free protoporphyrin in erythrocytes by acetone extraction","volume":"27","author":"D Hart","year":"1981","journal-title":"Clin Chem"},{"key":"pone.0262487.ref018","first-page":"1","volume-title":"Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity","author":"World Health Organization","year":"2011"},{"key":"pone.0262487.ref019","article-title":"Prevalence and Predictive Value of Anemia and Dysregulated Iron Homeostasis in Patients with COVID-19 Infection","author":"R Bellmann-Weiler","year":"2020","journal-title":"Journal of Clinical Medicine"},{"key":"pone.0262487.ref020","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1186\/s12879-021-05868-4","article-title":"Anemia predicts poor outcomes of COVID-19 in hospitalized patients: a prospective study in Iran","volume":"21","author":"M Faghih Dinevari","year":"2021","journal-title":"BMC Infect Dis"},{"key":"pone.0262487.ref021","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1053\/j.seminhematol.2009.06.001","article-title":"Iron sequestration and anemia of inflammation","volume":"46","author":"T Ganz","year":"2009","journal-title":"Semin Hematol"},{"key":"pone.0262487.ref022","doi-asserted-by":"crossref","first-page":"4617","DOI":"10.3748\/wjg.15.4617","article-title":"An update on iron physiology","volume":"15","author":"M Mu\u00f1oz","year":"2009","journal-title":"World J Gastroenterol"},{"key":"pone.0262487.ref023","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1182\/blood.V81.5.1200.1200","article-title":"Zinc protoporphyrin in anemia of chronic disorders","volume":"81","author":"J Hastka","year":"1993","journal-title":"Blood"},{"key":"pone.0262487.ref024","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s40635-019-0261-2","article-title":"Development of a model for anemia of inflammation that is relevant to critical care","volume":"7","author":"M Boshuizen","year":"2019","journal-title":"Intensive Care Med Exp"},{"key":"pone.0262487.ref025","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.htct.2020.03.001","article-title":"Hemoglobin value may be decreased in patients with severe coronavirus disease 2019","author":"G Lippi","year":"2020","journal-title":"Hematology, transfusion and cell therapy"},{"key":"pone.0262487.ref026","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/s10238-020-00679-4","article-title":"Anemia in patients with Covid-19: pathogenesis and clinical significance","volume":"21","author":"G Bergamaschi","year":"2021","journal-title":"Clin Exp Med"},{"key":"pone.0262487.ref027","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s00277-020-04256-3","article-title":"Prognostic significance of hemoglobin level and autoimmune hemolytic anemia in SARS-CoV-2 infection","volume":"100","author":"AA Algassim","year":"2021","journal-title":"Ann Hematol"},{"key":"pone.0262487.ref028","doi-asserted-by":"crossref","first-page":"e194","DOI":"10.1002\/hsr2.194","article-title":"Leukocytosis and alteration of hemoglobin level in patients with severe COVID-19: Association of leukocytosis with mortality","volume":"3","author":"B Sayad","year":"2020","journal-title":"Heal Sci reports"},{"key":"pone.0262487.ref029","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1002\/jmv.25839","article-title":"Does recombinant human erythropoietin administration in critically ill COVID-19 patients have miraculous therapeutic effects?","volume":"92","author":"A Hadadi","year":"2020","journal-title":"J Med Virol"},{"key":"pone.0262487.ref030","first-page":"1","article-title":"Depriving Iron Supply to the Virus Represents a Promising Adjuvant Therapeutic Against Viral Survival","author":"W Liu","year":"2020","journal-title":"Curr Clin Microbiol reports"},{"key":"pone.0262487.ref031","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.jmii.2020.10.001","article-title":"Desaturation and heme elevation during COVID-19 infection: A potential prognostic factor of heme oxygenase-1","volume":"54","author":"W-L Su","year":"2021","journal-title":"J Microbiol Immunol Infect"},{"key":"pone.0262487.ref032","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1021\/acsptsci.0c00136","article-title":"Heme\/Hemeoxygenase-1 System Is a Potential Therapeutic Intervention for COVID-19 Patients with Severe Complications","volume":"3","author":"BK Maiti","year":"2020","journal-title":"ACS Pharmacol Transl Sci"},{"key":"pone.0262487.ref033","article-title":"Blood management during the COVID-19 pandemic","author":"D Tolich","year":"2020","journal-title":"Cleve Clin J Med"},{"key":"pone.0262487.ref034","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.kint.2020.04.017","article-title":"Could ferritin help the screening for COVID-19 in hemodialysis patients?","volume":"98","author":"S Bataille","year":"2020","journal-title":"Kidney Int"},{"key":"pone.0262487.ref035","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.ijid.2020.04.061","article-title":"Mild versus severe COVID-19: Laboratory markers","volume":"95","author":"TP Velavan","year":"2020","journal-title":"Int J Infect Dis"},{"key":"pone.0262487.ref036","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.cca.2020.06.033","article-title":"Hyperferritinemia in critically ill COVID-19 patients\u2014Is ferritin the product of inflammation or a pathogenic mediator?","volume":"509","author":"J G\u00f3mez-Pastora","year":"2020","journal-title":"Clin Chim Acta"},{"issue":"Suppl 1","key":"pone.0262487.ref037","doi-asserted-by":"crossref","first-page":"S37","DOI":"10.1111\/hdi.12543","article-title":"Role of hepcidin-ferroportin axis in the pathophysiology, diagnosis, and treatment of anemia of chronic inflammation","volume":"21","author":"AL Langer","year":"2017","journal-title":"Hemodial Int"},{"key":"pone.0262487.ref038","first-page":"E32","article-title":"Hepcidin levels predict Covid-19 severity and mortality in a cohort of hospitalized Italian patients","author":"A Nai","year":"2021","journal-title":"American journal of hematology. United States"},{"key":"pone.0262487.ref039","doi-asserted-by":"crossref","first-page":"e926178","DOI":"10.12659\/MSM.926178","article-title":"Increased Serum Levels of Hepcidin and Ferritin Are Associated with Severity of COVID-19","volume":"26","author":"C Zhou","year":"2020","journal-title":"Med Sci Monit"},{"key":"pone.0262487.ref040","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.clinbiochem.2003.10.006","article-title":"Iron assessment tests: transferrin receptor vis-\u00e0-vis zinc protoporphyrin","volume":"37","author":"RF Labb\u00e9","year":"2004","journal-title":"Clin Biochem"},{"key":"pone.0262487.ref041","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1093\/clinchem\/40.5.768","article-title":"Central role of zinc protoporphyrin in staging iron deficiency","volume":"40","author":"J Hastka","year":"1994","journal-title":"Clin Chem"},{"key":"pone.0262487.ref042","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/0009-8981(95)06200-9","article-title":"Detection of iron-deficiency anemia in hospitalized patients by zinc protoporphyrin","volume":"244","author":"SS Wong","year":"1996","journal-title":"Clin Chim Acta"},{"key":"pone.0262487.ref043","doi-asserted-by":"crossref","first-page":"256","DOI":"10.3109\/10408363.2015.1038744","article-title":"Diagnosis of iron-deficient states","volume":"52","author":"NM Archer","year":"2015","journal-title":"Crit Rev Clin Lab Sci"},{"key":"pone.0262487.ref044","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1093\/clinchem\/26.3.409","article-title":"Hemoglobin determined in 15 microL of whole blood by \u201cfront-face\u201d fluorometry","volume":"26","author":"WE Blumberg","year":"1980","journal-title":"Clin Chem"},{"issue":"2","key":"pone.0262487.ref045","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/sj.thj.6200156","article-title":"The utility of the zinc-protoporphyrin assay as an initial screen for iron-deficient erythropoiesis","volume":"3","author":"B Myers","year":"2002","journal-title":"The hematology journal: the official journal of the European Haematology Association"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0262487","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,16]],"date-time":"2023-11-16T22:37:05Z","timestamp":1700174225000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0262487"}},"subtitle":[],"editor":[{"given":"Colin","family":"Johnson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,2,3]]},"references-count":45,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2,3]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0262487","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,3]]}}}