Prognostic Value of Nucleated Red Blood Cells in Patients with Acute Pancreatitis in the Emergency Department: A Single-Center Retrospective Study

Prognostic Value of Nucleated Red Blood Cells in Patients with Acute Pancreatitis in the Emergency Department: A Single-Center Retrospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Prognostic Value of Nucleated Red Blood Cells in Patients with Acute Pancreatitis in the Emergency Department: A Single-Center Retrospective Study Ezgi Ünal, Hüseyin Narcı, Cüneyt Ayrık, Semra Erdoğan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6014254/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Aim : In this study, we sought to investigate the success of nucleated red blood cells (NRBCs ) in predicting disease severity and mortality in patients with AP. Methods: This single-center, retrospective study was conducted in AP patients admitted to the emergency department. NRBCs values and other laboratory data were recorded in the study form. Patients were divided into three groups according to disease severity (mild, moderate and severe) and two groups according to outcome (survivors and non-survivors). Results: Half of the 296 patients included in the study were male and the mean age was 55.6±17.9 years. NRBCs values were higher in severe cases than in mild and moderate groups. In the Receiver operating characteristic (ROC) analysis performed to determine disease severity, the specificity, sensitivity and area under curve (AUC) values for NRBCs were 58,8%, 91.8%, and 0.755, respectively. The NRBCs values were higher in non-survivors patients than in survivors patients. In the ROC analysis performed to detect non-survivors patients, the specificity sensitivity and AUC values for NRBCs were 63,6%, 90,9% and 0.770, respectively. Conclusion: In AP patients, high NRBCs levels may be successful in predicting both disease severity and mortality. However, more studies are needed for clinical use Nucleated Red Blood Cell Pancreatitis Prognosis Mortality Figures Figure 1 1. Introduction It is important to predict the prognosis of many diseases in emergency departments. Acute pancreatitis (AP) is one of the most important of these diseases. AP is a disease with a wide clinical spectrum that can cause mild abdominal pain and multiple organ dysfunction, resulting in death( 1 ). Many laboratory parameters and scoring systems are available to diagnose, classify and monitor the progression of AP, but these parameters are time consuming and economically expensive( 2 ). Therefore, there is still a need for rapid, inexpensive parameters with high diagnostic value Nucleated red blood cells (NRBCs) are early erythrocyte precursors that are rarely found in the circulation of healthy adults ( 3 ). Normally, they are found in the bone marrow of humans of all ages. Here, they differentiate into a common myleoid progenitor cell and eventually into an advanced cell structure to become an erythroblast ( 4 ). At this stage, the cell loses its nucleus and becomes a reticulocyte. After this stage, the cell becomes a mature erythrocyte ( 5 ). NRBCs are present in the circulation during the fetal period and are reported to disappear in the first month of life in healthy newborns ( 6 , 7 ). In the literature, there are reports that NRBCs occur in peripheral blood in patients with trauma, sepsis and similar critical conditions and are associated with mortality ( 8 ). In addition, it is also used diagnostically in hematologic diseases ( 9 ). In recent years, research on the role of NRBCs in understanding the pathophysiology of inflammatory diseases has been increasing. Especially in severe inflammatory conditions such as acute pancreatitis, the presence and levels of NRBCs may provide valuable information about the severity and prognosis of the disease. The aim of this study was to evaluate the presence and levels of NRBCs in the peripheral blood circulation of patients with acute pancreatitis. Understanding the possible effects of NRBCs levels on the pathophysiology and prognosis of AP may contribute to the development of new approaches in the management of patients. 2. Materials and Methods 2.1.Study Design Patients diagnosed with acute pancreatitis admitted to the emergency department between 01.12.2019 and 01.12.2023 were included in the study. Demographic data (age, gender), laboratory values (leukocytes, neutrophils, lymphocytes, hemoglobin (Hgb), red cell distribution width (RDW), NRBCs, C-reactive protein (CRP), glucose, urea, creatinine, aspartate transaminase (AST), alanine transaminase (ALT), lacticdehigrogenase (LDH), amylase, lipase), etiology of pancreatitis, disease severity classification, clinical outcomes (survivors, non-survivors) were recorded on the data form. The data of the patients were retrospectively analyzed through the hospital automation system. Ethics committee approval for our study was obtained from Mersin University, Clinical Research Ethics Committee with the decision dated 27.12.2023 and numbered 2023/896. Patients under the age of 18, those with incomplete laboratory data, a history of active malignancy, hematological disorders, end-stage renal failure, cirrhosis, those receiving chemotherapy, and patients who have received a blood transfusion within the last 3 months without presenting to the emergency department were excluded from the study. A total of 313 patients with acute pancreatitis were evaluated. Among these patients, 17 patients with incomplete data, chemotherapy or blood transfusion history in the last month, active malignancy history, hematologic pathology diagnosis (leukemia, lymphoma, etc.) and under 18 years of age were excluded from the study. The study was performed with 296 patients who met the inclusion criteria. 2.2. Laboratory examination Blood samples were collected in EDTA tubes for the analysis of leukocyte count, hemoglobin (Hb) concentration, red cell distribution width (RDW), and nucleated red blood cells (NRBCs). The measurements were subsequently performed using an automated hematology analyzer (XN-1000, Sysmex Corp., Kobe, Japan). The normal reference ranges for these parameters, as established in our study, were as follows:Leukocyte count: 4,500–11,000 cells/mm³, Hemoglobin (Hb): 12.6–17.4 g/dL, Red Cell Distribution Width (RDW): 11.6–14.8%, Nucleated Red Blood Cells (NRBCs): 0.03–0.11 x 10³/µL,. These reference values were based on the population characteristics of the study cohort, and all measurements were conducted in accordance with standard laboratory procedures to ensure accuracy and reliability of the results. 2.3. Statistical Analysis Normality controls of continuous measurements were tested with Shapiro Wilk test. For comparisons in terms of the degree of severity, analysis of variance was used for normally distributed variables and Kruskall Wallis tests were used for non-normally distributed parameters. Levene's test was used for homogeneity of variances in normally distributed parameters. Under the condition of homogeneity of variances, One Way ANOVA test was used for intergroup comparisons and Bonferroni test was used for pairwise comparisons. For the parameters that did not meet the homogeneity of variances condition, intergroup differences were tested with Welch test and pairwise comparisons were tested with Games Howell test. In pairwise comparisons of continuous measurements, Student t test was used for normally distributed variables and Mann Whitney U test was used for non-normally distributed parameters. Mean, standard deviation, median and 25–75% percentages were given as descriptive statistics. Pearson chi-square, Fisher Exact chi-square and Likelihood Ratio chi-square tests were used for differences with categorical variables. Number and percentage values are given as descriptive statistics. Cut-off points for continuous parameters were obtained using ROC analysis. Cut points, sensitivity, selectivity, positive and negative predictive values are given as descriptive statistics. For all tests, p < 0.05 was taken for statistical significance. 3. Results Distribution of demographic and clinical data of the patients A total of 296 patients were included in the study. The cohort was evenly distributed by sex, with 50% (n = 148) male and 50% (n = 148) female patients. The mean age of the patients was 55.6 ± 17.9 years. Regarding the etiology of acute pancreatitis (AP), the contributing factors were as follows: 1.4% (n = 4) of patients had a history of alcohol consumption, 56.4% (n = 167) had biliary pathology, 11.5% (n = 34) had hypertriglyceridemia, and 30.7% (n = 91) had other etiological factors, including post-endoscopic retrograde cholangiopancreatography (ERCP), pancreatic duct obstructions (due to malignancy or strictures), and idiopathic causes. Patients were classified according to the Revised Atlanta criteria into mild, moderate, and severe categories. It was determined that 80.1% (n = 237) of the patients had mild AP, 14.2% (n = 42) had moderate AP, and 5.7% (n = 17) had severe AP (Table 1). Comparison of laboratory values according to severity of acute pancreatitis Laboratory parameters were compared between mild, moderate, and severe groups according to the severity of acute pancreatitis (AP). No significant differences were found between leukocyte, neutrophil, lymphocyte, hemoglobin (Hgb), neutrophil/lymphocyte ratio (NLR), glucose, AST, ALT, amylase, lipase, and LDH levels with respect to disease severity. However, nucleated red blood cells (NRBCs), red cell distribution width (RDW), C-reactive protein (CRP), urea and creatinine levels were significantly higher in the severe disease group. (Table 2). Comparison of laboratory values between surviving and non-surviving patients When laboratory parameters were compared between survivors and non-survivors patients, no significant differences were observed in the levels of leukocytes, neutrophils, lymphocytes, hemoglobin (Hb), neutrophil-to-lymphocyte ratio (NLR), glucose, aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase, lipase, and lactate dehydrogenase (LDH). However, in non-survivors patients, the levels of nucleated red blood cells (NRBCs), red cell distribution width (RDW), C-reactive protein (CRP), urea, and creatinine were significantly higher (Table 3). Receiver operator curve (ROC) analysis for the performance of laboratory parameters in predicting AP severity and outcome The ability of laboratory parameters showing significant differences to predict the severity and outcome of the disease was evaluated using Receiver Operating Characteristic (ROC) curve analysis. Among the parameters, nucleated red blood cells (NRBCs) demonstrated a notable predictive capacity for disease severity. The specificity, sensitivity, and area under the curve (AUC) values for NRBCs in predicting disease severity were found to be 58.8%, 91.8%, and 0.755, respectively. When compared to other parameters, NRBCs exhibited the highest AUC for predicting disease severity (AUC: 0.755; 95% Confidence Interval [CI]: 0.602–0.908; p = 0.001). Furthermore, in distinguishing between survivors and non-survivors patients, NRBCs showed a specificity of 63.6%, sensitivity of 90.9%, and an AUC value of 0.770 (Table 4, Fig. 1 ). 4. Discussion Acute pancreatitis is an abrupt inflammation of the pancreas, typically characterized by severe abdominal pain, nausea, and vomiting. This condition can result from various etiological factors including gallstones, excessive alcohol consumption, and certain medications, leading to significant morbidity and mortality rates( 1 , 2 ). An important finding of this study suggests that high NRBCs counts may be associated with disease severity and mortality, thus providing clinicians with a non-invasive tool to assess prognosis and guide treatment strategies in this challenging clinical context. Nucleated red blood cells (NRBCs) are a newly studied inflammatory biomarker in adult patients. It has been reported that some immune-related biological processes (such as phagocytosis, antigen presentation, interleukin production, etc.) are associated with NRBCs( 10 , 11 ). In a study conducted by Stachon et al., it was found that elevated levels of NRBCs in the blood are associated with increased mortality in critically ill patients, indicating that NRBCs are an independent risk factor for mortality( 12 ). Schmidt et al. reported that in their study of patients with COVID-19 who developed ARDS, NRBCs serve as a biomarker for predicting mortality in these patients( 13 ). Additionally, a study by Noor et al. reported that the presence and elevated levels of NRBCs in critically ill patients in the ICU serve as a biomarker for increased mortality( 14 ). As demonstrated by the studies mentioned above, research on nucleated red blood cells (NRBCs) points to their significant impact on the prognosis of patients in intensive care. However, our literature review revealed a limited number of studies investigating the relationship between NRBC levels and acute pancreatitis. One of these studies was conducted by Liu et al. and showed that NRBCs levels were significantly higher in non-surviving AP patients compared to survivors ( 15 ). In another study, Xu et al. reported that the presence of NRBCs was associated with increased mortality in cases of severe AP. However, they said that no prediction could be made regarding the severity of the disease ( 16 ). The correlation between nucleated red blood cell (NRBC) levels and patient outcomes in acute pancreatitis is increasingly recognized as a very important marker for assessing prognosis. Elevated levels of NRBCs may indicate an increased stress response in patients facing acute pancreatitis, potentially reflecting bone marrow activation in response to systemic inflammation. This phenomenon has been associated with several adverse outcomes, such as increased incidence of infectious complications and prolonged hospitalization. Prognostic evaluation of NRBCs in patients with acute pancreatitis, as can be seen from the above studies, the presence of NRBCs appears to be a valuable biomarker for prognostic outcomes in many critical illnesses, including acute pancreatitis. In our study, high NRBCs levels were found to be a successful biomarker that can be used to determine both disease severity and mortality in AP cases. Thus, monitoring NRBCs levels may serve as an invaluable tool in predicting patient prognosis, allow timely interventions to improve clinical outcomes, and inform treatment strategies in the management of acute pancreatitis. Limitations We have several limitations in our study. One of them is that our study was retrospective. Another limitation is that our study was conducted in a single center. Our last limitation is that the data of the patients who we did not include in our study because they met the exclusion criteria were not included in the study. We do not have clear information about whether there will be a change in our results due to the data of these patients. However, we think that these limitations are not at a level that would require reorganization or cause a change in our results. 5. Conclusion This study demonstrated that elevated NRBC levels were associated with increased disease severity and in-hospital mortality and may reveal their potential as effective biomarkers for identifying high-risk patients in emergency settings. Furthermore, integrating NRBCs assessments into existing prognostic models may increase the accuracy of risk stratification and ultimately improve patient outcomes. Although further research is required to solidify these findings and explore the underlying pathophysiological mechanisms, the current evidence positions NRBCs as a promising tool in the prognostic landscape of acute pancreatitis management. Declarations Ethical conduct of research The authors state that they have obtained appropriate institutional review board approval (Mersin University Clinical Research Ethics Committee with the decision dated 27.12.2023 and numbered 2023/896) and/or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved Author Contribution HN and EÜ conceived and designed the study. HN and CA conducted the acquisition of the data. SE provided methodological and statistical expertise. HN and EÜ analyzed and interpreted the data. CA, EÜ provided support with the literature search. HN, CA and EÜ provided content expertise about this topic. References Szatmary P, Grammatikopoulos T, Cai W, Huang W, Mukherjee R, Halloran C, et al. Acute Pancreatitis: Diagnosis and Treatment. Drugs. 2022;82(12):1251–1276. doi: 10.1007/s40265-022-01766-4 . Lee DW, Cho CM. Predicting Severity of Acute Pancreatitis. Medicina (Kaunas). 2022;58(6):787. doi: 10.3390/medicina58060787 . Chinudomwong P, Khongjaroensakun N, Chatachote B, et al. Improving the efficiency of the autoverification workflow for nucleated red blood cell reporting in the hematology laboratory. Int J Lab Hematol. 2021;43(6):1373–1378. doi: 10.1111/ijlh.13641 . Nandakumar SK, Ulirsch JC, Sankaran VG. Advances in understanding erythropoiesis: evolving perspectives. Br J Haematol. 2016;173(2):206–18. doi: 10.1111/bjh.13938 Tsiftsoglou AS. Erythropoietin (EPO) as a Key Regulator of Erythropoiesis, Bone Remodeling and Endothelial Transdifferentiation of Multipotent Mesenchymal Stem Cells (MSCs): Implications in Regenerative Medicine. Cells. 2021;10(8):2140. doi: 10.3390/cells10082140 . Aslam S, Molloy EJ. Biomarkers of multiorgan injury in neonatal encephalopathy. Biomark Med. 2015;9(3):267–75. doi: 10.2217/bmm.14.116 . Singh R, Hatt L, Ravn K, et al. Fetal cells in maternal blood for prenatal diagnosis: a love story rekindled. Biomark Med. 2017;11(9):705–710. doi: 10.2217/bmm-2017-0055 . Pikora K, Krętowska-Grunwald A, Krawczuk-Rybak M, Sawicka-Żukowska M. Diagnostic Value and Prognostic Significance of Nucleated Red Blood Cells (NRBCs) in Selected Medical Conditions. Cells. 202;12(14):1817. doi: 10.3390/cells12141817 Chikkodi SV, Malhotra P, Naseem S, et al. Factors Affecting Early Molecular Response in Chronic Myeloid Leukemia. Clin Lymphoma Myeloma Leuk. 2015;15 Suppl: S114-9. doi: 10.1016/j.clml.2015.03.014 . Passantino L, Massaro MA, Jirillo F, et al. Antigenically activated avian erythrocytes release cytokine-like factors: A conserved phylogenetic function discovered in fish. Immunopharmacol Immunotoxicol. 2007;29:141–52.doi: 10.1080/08923970701284664 Morera D, Roher N, Ribas L, et al. Rna-seq reveals an integrated immune response in nucleated erythrocytes. PLoS One. 2011;6:e26998. doi: 10.1371/journal.pone.0026998 . Stachon A, Bolulu O, Holland-Letz T,et al. Association between nucleated red blood cells in blood and the levels of erythropoietin, interleukin 3, interleukin 6, and interleukin 12p70. Shock. 2005; 24:34–39. doi: 1097/01.shk.0000164693.11649.91. Schmidt G, Martens A, Koch C, Markmann M, Schneck E, Matt U, et al. Nucleated red blood cells are a late biomarker in predicting intensive care unit mortality in patients with COVID-19 acute respiratory distress syndrome: an observational cohort study. Front Immunol. 2024; 15:1313977. doi: 10.3389/fimmu.2024.1313977 . Noor T, Imran A, Raza H, et al. Frequency of Nucleated Red Blood Cells in the Peripheral Blood of ICU-Admitted Patients. Cureus. 2023;15(1): e33827. doi: 10.7759/cureus.33827 Liu HQ, Wang GQ, Zhang CS, Wang X, Shi JK, Qu F, Ruan H. Nucleated red blood cell distribution in critically ill patients with acute pancreatitis: a retrospective cohort study. BMC Gastroenterol. 2024;24(1):353. doi: 10.1186/s12876-024-03444-z . Xu C, Wang J, Jin X, Yuan Y, Lu G. Establishment of a predictive model for outcomes in patients with severe acute pancreatitis by nucleated red blood cells combined with Charlson complication index and APACHE II score. Turk J Gastroenterol. 2020;31(12):936–941. doi: 10.5152/tjg.2020.19954 . Tables Table 1 to 4 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Onlinefloatimage1.png Table 1 Onlinefloatimage2.png Table 2 Onlinefloatimage3.png Table 3 Onlinefloatimage4.png Table 4 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6014254","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":414737294,"identity":"8c8b1b9e-4db5-413b-9ebc-4a16c9fd8ddd","order_by":0,"name":"Ezgi Ünal","email":"","orcid":"","institution":"Osmaniye state hospital","correspondingAuthor":false,"prefix":"","firstName":"Ezgi","middleName":"","lastName":"Ünal","suffix":""},{"id":414737295,"identity":"80100a9c-66ca-4feb-90bf-91da95182086","order_by":1,"name":"Hüseyin Narcı","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxklEQVRIiWNgGAWjYBACAyjNww8iEwpI0SLZANJigEcpuhYGgwMoXDzAnP/ssQc/99jJGJ9fnfjhgQGDPL/YAfxaLGfkpRv2PEvmMbvxdrME0GGGM2cnEHDYDR4zCZ4DB4Bazm4AaUkwuE1Iy/kzZpJ/gFqMZ5zd/IM4LQdyzKRBthjw924j0pYbQC0yB5J5JG7wbrNIMJAgwi8gh705YGfP3392880fFTby/NIEtCCABFilBLHKQYD/ACmqR8EoGAWjYCQBAMJLQkZfK/oqAAAAAElFTkSuQmCC","orcid":"","institution":"Mersin University","correspondingAuthor":true,"prefix":"","firstName":"Hüseyin","middleName":"","lastName":"Narcı","suffix":""},{"id":414737296,"identity":"2df3c729-49b4-4110-906f-ec4428999d64","order_by":2,"name":"Cüneyt Ayrık","email":"","orcid":"","institution":"Mersin University","correspondingAuthor":false,"prefix":"","firstName":"Cüneyt","middleName":"","lastName":"Ayrık","suffix":""},{"id":414737297,"identity":"e12657a1-27d8-4876-a247-03579a2f4371","order_by":3,"name":"Semra Erdoğan","email":"","orcid":"","institution":"Mersin University","correspondingAuthor":false,"prefix":"","firstName":"Semra","middleName":"","lastName":"Erdoğan","suffix":""}],"badges":[],"createdAt":"2025-02-12 10:23:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6014254/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6014254/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":76297544,"identity":"a2f9ea48-c7c5-42db-9add-57c9a4d0ed63","added_by":"auto","created_at":"2025-02-14 13:27:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":96999,"visible":true,"origin":"","legend":"\u003cp\u003eReceiver operator curve (ROC) analysis for the performance of laboratory parameters in predicting AP severity and outcome \u003cstrong\u003eA.\u003c/strong\u003e AP severity, \u003cstrong\u003eB\u003c/strong\u003e. 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Introduction","content":"\u003cp\u003eIt is important to predict the prognosis of many diseases in emergency departments. Acute pancreatitis (AP) is one of the most important of these diseases. AP is a disease with a wide clinical spectrum that can cause mild abdominal pain and multiple organ dysfunction, resulting in death(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Many laboratory parameters and scoring systems are available to diagnose, classify and monitor the progression of AP, but these parameters are time consuming and economically expensive(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Therefore, there is still a need for rapid, inexpensive parameters with high diagnostic value\u003c/p\u003e \u003cp\u003eNucleated red blood cells (NRBCs) are early erythrocyte precursors that are rarely found in the circulation of healthy adults (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Normally, they are found in the bone marrow of humans of all ages. Here, they differentiate into a common myleoid progenitor cell and eventually into an advanced cell structure to become an erythroblast (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). At this stage, the cell loses its nucleus and becomes a reticulocyte. After this stage, the cell becomes a mature erythrocyte (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). NRBCs are present in the circulation during the fetal period and are reported to disappear in the first month of life in healthy newborns (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). In the literature, there are reports that NRBCs occur in peripheral blood in patients with trauma, sepsis and similar critical conditions and are associated with mortality (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). In addition, it is also used diagnostically in hematologic diseases (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). In recent years, research on the role of NRBCs in understanding the pathophysiology of inflammatory diseases has been increasing. Especially in severe inflammatory conditions such as acute pancreatitis, the presence and levels of NRBCs may provide valuable information about the severity and prognosis of the disease.\u003c/p\u003e \u003cp\u003eThe aim of this study was to evaluate the presence and levels of NRBCs in the peripheral blood circulation of patients with acute pancreatitis. Understanding the possible effects of NRBCs levels on the pathophysiology and prognosis of AP may contribute to the development of new approaches in the management of patients.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1.Study Design\u003c/h2\u003e \u003cp\u003ePatients diagnosed with acute pancreatitis admitted to the emergency department between 01.12.2019 and 01.12.2023 were included in the study. Demographic data (age, gender), laboratory values (leukocytes, neutrophils, lymphocytes, hemoglobin (Hgb), red cell distribution width (RDW), NRBCs, C-reactive protein (CRP), glucose, urea, creatinine, aspartate transaminase (AST), alanine transaminase (ALT), lacticdehigrogenase (LDH), amylase, lipase), etiology of pancreatitis, disease severity classification, clinical outcomes (survivors, non-survivors) were recorded on the data form. The data of the patients were retrospectively analyzed through the hospital automation system. Ethics committee approval for our study was obtained from Mersin University, Clinical Research Ethics Committee with the decision dated 27.12.2023 and numbered 2023/896.\u003c/p\u003e \u003cp\u003ePatients under the age of 18, those with incomplete laboratory data, a history of active malignancy, hematological disorders, end-stage renal failure, cirrhosis, those receiving chemotherapy, and patients who have received a blood transfusion within the last 3 months without presenting to the emergency department were excluded from the study.\u003c/p\u003e \u003cp\u003eA total of 313 patients with acute pancreatitis were evaluated. Among these patients, 17 patients with incomplete data, chemotherapy or blood transfusion history in the last month, active malignancy history, hematologic pathology diagnosis (leukemia, lymphoma, etc.) and under 18 years of age were excluded from the study. The study was performed with 296 patients who met the inclusion criteria.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Laboratory examination\u003c/h2\u003e \u003cp\u003eBlood samples were collected in EDTA tubes for the analysis of leukocyte count, hemoglobin (Hb) concentration, red cell distribution width (RDW), and nucleated red blood cells (NRBCs). The measurements were subsequently performed using an automated hematology analyzer (XN-1000, Sysmex Corp., Kobe, Japan). The normal reference ranges for these parameters, as established in our study, were as follows:Leukocyte count: 4,500\u0026ndash;11,000 cells/mm\u0026sup3;, Hemoglobin (Hb): 12.6\u0026ndash;17.4 g/dL, Red Cell Distribution Width (RDW): 11.6\u0026ndash;14.8%, Nucleated Red Blood Cells (NRBCs): 0.03\u0026ndash;0.11 x 10\u0026sup3;/\u0026micro;L,. These reference values were based on the population characteristics of the study cohort, and all measurements were conducted in accordance with standard laboratory procedures to ensure accuracy and reliability of the results.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Statistical Analysis\u003c/h2\u003e \u003cp\u003eNormality controls of continuous measurements were tested with Shapiro Wilk test. For comparisons in terms of the degree of severity, analysis of variance was used for normally distributed variables and Kruskall Wallis tests were used for non-normally distributed parameters. Levene's test was used for homogeneity of variances in normally distributed parameters. Under the condition of homogeneity of variances, One Way ANOVA test was used for intergroup comparisons and Bonferroni test was used for pairwise comparisons. For the parameters that did not meet the homogeneity of variances condition, intergroup differences were tested with Welch test and pairwise comparisons were tested with Games Howell test. In pairwise comparisons of continuous measurements, Student t test was used for normally distributed variables and Mann Whitney U test was used for non-normally distributed parameters. Mean, standard deviation, median and 25\u0026ndash;75% percentages were given as descriptive statistics. Pearson chi-square, Fisher Exact chi-square and Likelihood Ratio chi-square tests were used for differences with categorical variables. Number and percentage values are given as descriptive statistics. Cut-off points for continuous parameters were obtained using ROC analysis. Cut points, sensitivity, selectivity, positive and negative predictive values are given as descriptive statistics.\u003c/p\u003e \u003cp\u003eFor all tests, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was taken for statistical significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003e \u003cb\u003eDistribution of demographic and clinical data of the patients\u003c/b\u003e \u003c/p\u003e \u003cp\u003eA total of 296 patients were included in the study. The cohort was evenly distributed by sex, with 50% (n\u0026thinsp;=\u0026thinsp;148) male and 50% (n\u0026thinsp;=\u0026thinsp;148) female patients. The mean age of the patients was 55.6\u0026thinsp;\u0026plusmn;\u0026thinsp;17.9 years. Regarding the etiology of acute pancreatitis (AP), the contributing factors were as follows: 1.4% (n\u0026thinsp;=\u0026thinsp;4) of patients had a history of alcohol consumption, 56.4% (n\u0026thinsp;=\u0026thinsp;167) had biliary pathology, 11.5% (n\u0026thinsp;=\u0026thinsp;34) had hypertriglyceridemia, and 30.7% (n\u0026thinsp;=\u0026thinsp;91) had other etiological factors, including post-endoscopic retrograde cholangiopancreatography (ERCP), pancreatic duct obstructions (due to malignancy or strictures), and idiopathic causes. Patients were classified according to the Revised Atlanta criteria into mild, moderate, and severe categories. It was determined that 80.1% (n\u0026thinsp;=\u0026thinsp;237) of the patients had mild AP, 14.2% (n\u0026thinsp;=\u0026thinsp;42) had moderate AP, and 5.7% (n\u0026thinsp;=\u0026thinsp;17) had severe AP (Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003e \u003cb\u003eComparison of laboratory values according to severity of acute pancreatitis\u003c/b\u003e \u003c/p\u003e \u003cp\u003eLaboratory parameters were compared between mild, moderate, and severe groups according to the severity of acute pancreatitis (AP). No significant differences were found between leukocyte, neutrophil, lymphocyte, hemoglobin (Hgb), neutrophil/lymphocyte ratio (NLR), glucose, AST, ALT, amylase, lipase, and LDH levels with respect to disease severity. However, nucleated red blood cells (NRBCs), red cell distribution width (RDW), C-reactive protein (CRP), urea and creatinine levels were significantly higher in the severe disease group. (Table\u0026nbsp;2).\u003c/p\u003e \u003cp\u003e \u003cb\u003eComparison of laboratory values between surviving and non-surviving patients\u003c/b\u003e \u003c/p\u003e \u003cp\u003eWhen laboratory parameters were compared between survivors and non-survivors patients, no significant differences were observed in the levels of leukocytes, neutrophils, lymphocytes, hemoglobin (Hb), neutrophil-to-lymphocyte ratio (NLR), glucose, aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase, lipase, and lactate dehydrogenase (LDH). However, in non-survivors patients, the levels of nucleated red blood cells (NRBCs), red cell distribution width (RDW), C-reactive protein (CRP), urea, and creatinine were significantly higher (Table\u0026nbsp;3).\u003c/p\u003e \u003cp\u003e \u003cb\u003eReceiver operator curve (ROC) analysis for the performance of laboratory parameters in predicting AP severity and outcome\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe ability of laboratory parameters showing significant differences to predict the severity and outcome of the disease was evaluated using Receiver Operating Characteristic (ROC) curve analysis. Among the parameters, nucleated red blood cells (NRBCs) demonstrated a notable predictive capacity for disease severity. The specificity, sensitivity, and area under the curve (AUC) values for NRBCs in predicting disease severity were found to be 58.8%, 91.8%, and 0.755, respectively. When compared to other parameters, NRBCs exhibited the highest AUC for predicting disease severity (AUC: 0.755; 95% Confidence Interval [CI]: 0.602\u0026ndash;0.908; p\u0026thinsp;=\u0026thinsp;0.001). Furthermore, in distinguishing between survivors and non-survivors patients, NRBCs showed a specificity of 63.6%, sensitivity of 90.9%, and an AUC value of 0.770 (Table\u0026nbsp;4, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eAcute pancreatitis is an abrupt inflammation of the pancreas, typically characterized by severe abdominal pain, nausea, and vomiting. This condition can result from various etiological factors including gallstones, excessive alcohol consumption, and certain medications, leading to significant morbidity and mortality rates(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). An important finding of this study suggests that high NRBCs counts may be associated with disease severity and mortality, thus providing clinicians with a non-invasive tool to assess prognosis and guide treatment strategies in this challenging clinical context.\u003c/p\u003e \u003cp\u003eNucleated red blood cells (NRBCs) are a newly studied inflammatory biomarker in adult patients. It has been reported that some immune-related biological processes (such as phagocytosis, antigen presentation, interleukin production, etc.) are associated with NRBCs(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). In a study conducted by Stachon et al., it was found that elevated levels of NRBCs in the blood are associated with increased mortality in critically ill patients, indicating that NRBCs are an independent risk factor for mortality(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Schmidt et al. reported that in their study of patients with COVID-19 who developed ARDS, NRBCs serve as a biomarker for predicting mortality in these patients(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Additionally, a study by Noor et al. reported that the presence and elevated levels of NRBCs in critically ill patients in the ICU serve as a biomarker for increased mortality(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAs demonstrated by the studies mentioned above, research on nucleated red blood cells (NRBCs) points to their significant impact on the prognosis of patients in intensive care. However, our literature review revealed a limited number of studies investigating the relationship between NRBC levels and acute pancreatitis. One of these studies was conducted by Liu et al. and showed that NRBCs levels were significantly higher in non-surviving AP patients compared to survivors (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e15\u003c/span\u003e). In another study, Xu et al. reported that the presence of NRBCs was associated with increased mortality in cases of severe AP. However, they said that no prediction could be made regarding the severity of the disease (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e16\u003c/span\u003e). The correlation between nucleated red blood cell (NRBC) levels and patient outcomes in acute pancreatitis is increasingly recognized as a very important marker for assessing prognosis. Elevated levels of NRBCs may indicate an increased stress response in patients facing acute pancreatitis, potentially reflecting bone marrow activation in response to systemic inflammation. This phenomenon has been associated with several adverse outcomes, such as increased incidence of infectious complications and prolonged hospitalization. Prognostic evaluation of NRBCs in patients with acute pancreatitis, as can be seen from the above studies, the presence of NRBCs appears to be a valuable biomarker for prognostic outcomes in many critical illnesses, including acute pancreatitis. In our study, high NRBCs levels were found to be a successful biomarker that can be used to determine both disease severity and mortality in AP cases. Thus, monitoring NRBCs levels may serve as an invaluable tool in predicting patient prognosis, allow timely interventions to improve clinical outcomes, and inform treatment strategies in the management of acute pancreatitis.\u003c/p\u003e \u003cp\u003e \u003cb\u003eLimitations\u003c/b\u003e \u003c/p\u003e \u003cp\u003eWe have several limitations in our study. One of them is that our study was retrospective. Another limitation is that our study was conducted in a single center. Our last limitation is that the data of the patients who we did not include in our study because they met the exclusion criteria were not included in the study. We do not have clear information about whether there will be a change in our results due to the data of these patients. However, we think that these limitations are not at a level that would require reorganization or cause a change in our results.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis study demonstrated that elevated NRBC levels were associated with increased disease severity and in-hospital mortality and may reveal their potential as effective biomarkers for identifying high-risk patients in emergency settings. Furthermore, integrating NRBCs assessments into existing prognostic models may increase the accuracy of risk stratification and ultimately improve patient outcomes. Although further research is required to solidify these findings and explore the underlying pathophysiological mechanisms, the current evidence positions NRBCs as a promising tool in the prognostic landscape of acute pancreatitis management.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthical conduct of research\u003c/h2\u003e\n\u003cp\u003eThe authors state that they have obtained appropriate institutional review board approval (Mersin University Clinical Research Ethics Committee with the decision dated 27.12.2023 and numbered 2023/896) and/or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eHN and E\u0026Uuml; conceived and designed the study. HN and CA conducted the acquisition of the data. SE provided methodological and statistical expertise. HN and E\u0026Uuml; analyzed and interpreted the data. CA, E\u0026Uuml; provided support with the literature search. HN, CA and E\u0026Uuml; provided content expertise about this topic.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSzatmary P, Grammatikopoulos T, Cai W, Huang W, Mukherjee R, Halloran C, et al. Acute Pancreatitis: Diagnosis and Treatment. Drugs. 2022;82(12):1251\u0026ndash;1276. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s40265-022-01766-4\u003c/span\u003e\u003cspan address=\"10.1007/s40265-022-01766-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee DW, Cho CM. Predicting Severity of Acute Pancreatitis. 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Frequency of Nucleated Red Blood Cells in the Peripheral Blood of ICU-Admitted Patients. Cureus. 2023;15(1): e33827. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7759/cureus.33827\u003c/span\u003e\u003cspan address=\"10.7759/cureus.33827\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu HQ, Wang GQ, Zhang CS, Wang X, Shi JK, Qu F, Ruan H. Nucleated red blood cell distribution in critically ill patients with acute pancreatitis: a retrospective cohort study. BMC Gastroenterol. 2024;24(1):353. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12876-024-03444-z\u003c/span\u003e\u003cspan address=\"10.1186/s12876-024-03444-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu C, Wang J, Jin X, Yuan Y, Lu G. Establishment of a predictive model for outcomes in patients with severe acute pancreatitis by nucleated red blood cells combined with Charlson complication index and APACHE II score. Turk J Gastroenterol. 2020;31(12):936\u0026ndash;941. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5152/tjg.2020.19954\u003c/span\u003e\u003cspan address=\"10.5152/tjg.2020.19954\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Nucleated Red Blood Cell, Pancreatitis, Prognosis, Mortality","lastPublishedDoi":"10.21203/rs.3.rs-6014254/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6014254/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eAim\u003c/strong\u003e: In this study, we sought to investigate the success of nucleated red blood cells (NRBCs\u003csub\u003e \u003c/sub\u003e) in predicting disease severity and mortality in patients with AP.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e This single-center, retrospective study was conducted in AP patients admitted to the emergency department. NRBCs values and other laboratory data were recorded in the study form. Patients were divided into three groups according to disease severity (mild, moderate and severe) and two groups according to outcome (survivors and non-survivors). \u003cstrong\u003eResults: \u003c/strong\u003eHalf of the 296 patients included in the study were male and the mean age was 55.6±17.9 years.\u0026nbsp; NRBCs values were higher in severe cases than in mild and moderate groups. In the Receiver operating characteristic (ROC) analysis performed to determine disease severity, the specificity, sensitivity and area under curve (AUC) values for NRBCs were 58,8%, 91.8%, and 0.755, respectively. The NRBCs values were higher in non-survivors patients than in survivors patients. In the ROC analysis performed to detect non-survivors patients, the specificity sensitivity and AUC values for NRBCs were 63,6%, 90,9% and 0.770, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eIn AP patients, high NRBCs levels may be successful in predicting both disease severity and mortality. However, more studies are needed for clinical use\u003c/p\u003e","manuscriptTitle":"Prognostic Value of Nucleated Red Blood Cells in Patients with Acute Pancreatitis in the Emergency Department: A Single-Center Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-14 13:27:21","doi":"10.21203/rs.3.rs-6014254/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"26e07dcc-7d29-461b-9516-84e574baad7a","owner":[],"postedDate":"February 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-03-08T15:23:26+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-14 13:27:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6014254","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6014254","identity":"rs-6014254","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}