Association Between Neutrophil-Lymphocyte Ratio and Herpes Zoster Infection in 1688 Living Donor Liver Transplantation Recipients at a Large Single Center
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biomedicines Article Association between Neutrophil-Lymphocyte Ratio and Herpes Zoster Infection in 1688 Living Donor Liver Transplantation Recipients at a Large Single Center Ji-Hoon Sim, Young-Jin Moon, Sung-Hoon Kim, Kyoung-Sun Kim , Ju-Seung Lee, Jun-Gol Song * and Gyu-Sam Hwang Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; [email protected] (J.-H.S.); [email protected] (Y.-J.M.); [email protected] (S.-H.K.); [email protected] (K.-S.K.); [email protected] (J.-S.L.); [email protected] (G.-S.H.) * Correspondence: [email protected]; Tel.: +82-2-3010-3869 Abstract: Liver transplantation (LT) is closely associated with decreased immune function, a contrib- utor to herpes zoster (HZ). However, risk factors for HZ in living donor LT (LDLT) remain unknown. Neutrophil-lymphocyte ratio (NLR) and immune system function are reportedly correlated. This study investigated the association between NLR and HZ in 1688 patients who underwent LDLT between January 2010 and July 2020 and evaluated risk factors for HZ and postherpetic neuralgia (PHN). The predictive power of NLR was assessed through the concordance index and an integrated discrimination improvement (IDI) analysis. Of the total cohort, 138 (8.2%) had HZ. The incidence of HZ after LT was 11.2 per 1000 person-years and 0.1%, 1.3%, 2.9%, and 13.5% at 1, 3, 5, and 10 years, Citation: Sim, J.-H.; Moon, Y.-J.; Kim, respectively. In the Cox regression analysis, preoperative NLR was significantly associated with HZ S.-H.; Kim, K.-S.; Lee, J.-S.; Song, J.-G.; (adjusted hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.02–1.09; p = 0.005) and PHN (HR, Hwang, G.-S. Association between 1.08; 95% CI, 1.03–1.13; p = 0.001). Age, sex, mycophenolate mofetil use, and hepatitis B virus infection Neutrophil-Lymphocyte Ratio and were risk factors for HZ versus age and sex for PHN. In the IDI analysis, NLR was discriminative for Herpes Zoster Infection in 1688 Living Donor Liver Transplantation HZ and PHN (p = 0.020 and p = 0.047, respectively). Preoperative NLR might predict HZ and PHN Recipients at a Large Single Center. in LDLT recipients. Biomedicines 2021, 9, 963. https:// doi.org/10.3390/biomedicines9080963 Keywords: herpes zoster; liver transplantation; living donor; neutrophil-lymphocyte ratio; posther- petic neuralgia Academic Editors: Anand Rotte and Sam Eldabe Received: 20 July 2021 1. Introduction Accepted: 4 August 2021 Herpes zoster (HZ) is a viral disease caused by varicella zoster virus (VZV) reac- Published: 5 August 2021 tivation and has an estimated incidence of 1.2–4.8 per 1000 individuals in the general population [1]. HZ is strongly associated with decreased immune function [2,3]; thus, it Publisher’s Note: MDPI stays neutral occurs mainly in elderly individuals [4–7], patients infected with human immunodeficiency with regard to jurisdictional claims in virus (HIV), and transplant recipients [8]. Previous studies reported that solid-organ trans- published maps and institutional affil- plant (SOT) recipients have a 2- to 10-fold higher risk of VZV reactivation than the general iations. population [9–11]. In particular, liver transplantation (LT) recipients are at increased risk of developing HZ due to a chronic immunosuppressed status [12,13]. Several studies reported postoperative HZ in SOT recipients [8–14]. In one study, the overall incidence of HZ after transplantation was 8.6% (liver, 5.7%; renal, 7.4%; lung, 15.1%; and heart, 16.8%) [15]. Copyright: © 2021 by the authors. Pergam and colleagues reported that LT patients generally require less immunosuppres- Licensee MDPI, Basel, Switzerland. sion because the liver is relatively resistant to rejection compared to other organs and that This article is an open access article the incidence of HZ is slightly lower than that of lung and heart transplant patients [11]. distributed under the terms and Nevertheless, the incidence of HZ in LT patients (up to 12%) is higher than that of the conditions of the Creative Commons Attribution (CC BY) license (https:// general patient group [12–14]. creativecommons.org/licenses/by/ Several recent reports stated that neutrophil-lymphocyte ratio (NLR) is associated 4.0/). with immune system function and the inflammatory response [16]. NLR is calculated Biomedicines 2021, 9, 963. https://doi.org/10.3390/biomedicines9080963 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, x FOR PEER REVIEW 2 of 12 Biomedicines 2021, 9, 963 Several recent reports stated that neutrophil-lymphocyte ratio (NLR) is associated2 of 11 with immune system function and the inflammatory response [16]. NLR is calculated as the ratio of the number of neutrophils and lymphocytes measured in the peripheral blood and reflects a patient’s inflammatory condition (neutrophil count) and adaptive immunity as the ratio of the number of neutrophils and lymphocytes measured in the peripheral (lymphocyte count). NLR is a simple and objective biomarker of patient survival and sur- blood and reflects a patient’s inflammatory condition (neutrophil count) and adaptive gical prognosis in various diseases, such as major cardiac disease and several cancers immunity (lymphocyte count). NLR is a simple and objective biomarker of patient survival [17,18]. and surgical prognosis in various diseases, such as major cardiac disease and several However, no studies to date have examined the association between preoperative cancers [17,18]. NLR and HZ. Therefore, in this study, we evaluated the association between preoperative However, no studies to date have examined the association between preoperative NLR and HZ development in patients who underwent living donor LT (LDLT). In addi- NLR and HZ. Therefore, in this study, we evaluated the association between preoperative tion, we assessed the association between preoperative NLR and postherpetic neuralgia NLR and HZ development in patients who underwent living donor LT (LDLT). In addition, (PHN) development, an advanced complication of HZ. we assessed the association between preoperative NLR and postherpetic neuralgia (PHN) development, an advanced complication of HZ. 2. Materials and Methods 2.1. 2.Study Materials Design andand MethodsPatients 2.1.This Study study Design was approved and Patients by the institutional review board of Asan Medical Center (protocolThis number: study 2021-0526), was approved which by waived the institutional the requirement reviewboard for written of Asan informed Medical con- Center sent(protocol due to its number: retrospective 2021-0526), design. which We waivedreviewed the the requirement data from for all writtenpatients informed who under- consent wentdue LDLT to its for retrospective end-stage liver design. disease We between reviewed January the data 2010 from and allJuly patients 2020. Adult who patients underwent agedLDLT ≥ 18 foryears end-stage were included liver disease in the between study. January 2010 and July 2020. Adult patients aged ≥The18 years exclusion were criteria included were in theas follows: study. (1) death within 4 weeks after LT; (2) presence of severeThe diseases exclusion such criteria as hematologic were as follows: disease, (1) inflammatory death within 4 disease, weeks after and LT; other (2) presence malig- of nancies;severe (3) diseases HIV infection; such as (4) hematologic insufficient disease, or no follow-up inflammatory data; disease, and (5) andincomplete other malignancies; medical record(3) HIVdata. infection; Based on (4)these insufficient criteria, a or total no of follow-up 1688 patients data; were and (5) enrolled incomplete and divided medical into record HZ data.(n = 138) Based and on non-HZ these criteria, (n = 1550) a total groups of1688 (Figure patients 1). were enrolled and divided into HZ (n = 138) and non-HZ (n = 1550) groups (Figure1). Figure 1. Flow chart of the study. Figure2.2. 1. Clinical Flow chart Data of Collectionthe study. and Outcome Assessments Demographic data and perioperative variables were collected from our institution’s medical record system. Demographic data included age, sex, body mass index (BMI), diabetes mellitus (DM), hypertension (HTN), coronary artery disease (CAD), Model for Biomedicines 2021, 9, 963 3 of 11 End-stage Liver Disease (MELD) score, and Child–Pugh classification. Data on ABO incom- patibility and retransplantation were also collected. Etiology-related variables included hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, alcoholic liver cirrho- sis, hepatocellular carcinoma (HCC), toxic hepatitis, and others. Donor-related variables included age, sex, and BMI. Preoperative laboratory values included white blood cell count and hemoglobin, international normalized ratio, fibrinogen, albumin, total bilirubin, sodium, and serum creatinine levels. Preoperative NLR, platelet-lymphocyte ratio (PLR), prognostic nutritional index (PNI), and C-reactive protein/albumin ratio were also collected. NLR was defined as the ratio between absolute neutrophil count versus absolute lymphocyte count, while PLR was defined as the ratio between absolute platelet count versus absolute lymphocyte count. PNI was calculated using serum albumin and total lymphocyte count [19]. Intraoperative variables included total ischemic time, post-reperfusion syndrome, graft- to-recipient weight ratio, and intraoperative transfusion requirement. Immunosuppressant- related variables included steroid, mycophenolate mofetil (MMF), cyclosporine, or tacrolimus use, and acute