Inflammation patterns in early postoperative cholangitis predict long-term outcomes in biliary atresia: A potential role of non-suppurative cholangitis

Inflammation patterns in early postoperative cholangitis predict long-term outcomes in biliary atresia: A potential role of non-suppurative cholangitis | 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 Inflammation patterns in early postoperative cholangitis predict long-term outcomes in biliary atresia: A potential role of non-suppurative cholangitis Toshio Harumatsu, Toshihiro Muraji, Ryuta Masuya, Yudai Tsuruno, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4689737/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Jul, 2024 Read the published version in Pediatric Surgery International → Version 1 posted 7 You are reading this latest preprint version Abstract Purpose Frequent postoperative cholangitis in biliary atresia (BA) affects the long-term native liver survival. This study assessed the characteristics of early cholangitis and their influence on the prognosis. Methods Forty-three patients with BA who underwent surgery between 2000 and 2020 were analyzed for routine inflammatory markers. Early cholangitis characteristics were compared between native liver survivor (NLS) and living donor liver transplant (LDLT) patients. Results Among the 43 patients, 30 (69.8%) experienced 130 episodes of cholangitis. In the area under the receiver operating characteristics curve (AUROC) analysis, the cutoff value of the total cholangitis episodes was 3, with an area under the AUROC curve of 0.695 (95% confidence interval: 0.522–0.868). Before 3 years old, 113 episodes (86.9%) of cholangitis were observed. The white blood cell, C-reactive protein, and alanine aminotransferase values at cholangitis onset did not markedly differ between the LDLT and NLS groups. Conversely, the neutrophil-to-lymphocyte ratio in the NLS group was significantly lower than in the LDLT group (0.85 vs. 1.63, p < 0.001). Conclusions Cholangitis in the NLS group was lymphocyte-dominant and atypical in its pathogenesis. Lymphocyte-dominant cholangitis is non-suppurative, and future research should clarify its pathogenesis to improve the treatment and prognosis of BA. biliary atresia cholangitis C-reactive protein neutrophil-lymphocyte ratio native liver survival rate Kasai portoenterostomy Figures Figure 1 Figure 2 Figure 3 Introduction Repeated episodes of cholangitis after Kasai portoenterostomy (KPE) adversely affect the outcome of patients with biliary atresia (BA) [ 1 ]. Possible predisposing factors for cholangitis include an insufficient volume of bile flow due to inherent hepato-cholangiopathy of the BA liver, temporary dehydration with reduced bile flow, and infection of the intrahepatic bile ducts due to bacteria ascending via the bilioenteric conduit with or without its obstruction [ 2 ]. Postoperative prophylactic intravenous antibiotic therapy did not decrease the incidence of cholangitis, even when administered for relatively long periods [ 3 ]. Previously adopted cholangitis-preventing surgical procedures, such as exteriorization of the Roux-en-Y limb or anti-reflux valve placement in the limb, have failed to decrease the number of cholangitis episodes [ 4 ]. Thus, the pathogenetic mechanism underlying postoperative cholangitis in BA may not be simple suppurative cholangitis due to ascending bacteria; rather, it may involve a more complex cholangiopathy. This study assessed the characteristics of cholangitis in the early postoperative period and their role in the prognosis. Methods 1.1. Study population The medical records of 43 patients with BA (male: female = 20:23) who underwent KPE at our institution from 2000 to 2020 were reviewed to investigate the relationship between inflammatory biomarkers and outcomes at the onset of cholangitis. Biomarkers included the white blood cell (WBC) count, neutrophil-to-lymphocyte ratio (NLR), lymphocyte ratio (lymphocytes in the total WBC count), and C-reactive protein (CRP), total bilirubin (TB), alanine aminotransferase (ALT), and γ-glutamyl transferase (γ-GTP) levels. First, we focused on the number of cholangitis episodes in each patient in all episodes of cholangitis occurring in the native liver. Then, we focused on the inflammatory biomarkers of cholangitis before three years old. Each parameter at the onset of all episodes of cholangitis was compared between patients with native liver survival (NLS) and living-donor liver transplant (LDLT). 1.2. Surgical and postoperative management The KPE procedure performed in this series included reconstruction with a long Roux-en-Y jejunal limb (60 cm) following portal dissection. Postoperative management included the administration of ursodeoxycholic acid and methylprednisolone (initial dose: 4 mg/kg/day) starting intravenously on postoperative day (POD) 2 for 5 days, followed by 2 mg/kg/day for 5 days, followed by oral prednisone (2 mg/kg/day) every other day for 2 months. In addition to this regimen, the patients received sulbactam sodium 80 mg/kg/day intravenously postoperatively. After the initiation of oral intake, the regimen was switched to cefdinir (10 mg/kg/day) to further reduce the risk of post-operative cholangitis. 1.3. Definition and treatment for cholangitis We focused on inflammatory biomarkers of cholangitis. Cholangitis was defined as a febrile episode with a body temperature of ≥38 °C without other obvious clinical sources of infection, as well as a combination of clinical findings. Clinical findings included the elevation of direct bilirubin at least >1 mg/dL above the previous baseline and an ALT or γ-GTP level increase to ≥2 or 1.5 times the upper limit of normal, respectively [5]. Blood culture tests were not included in the results of this study because they were rarely performed in this study period. Cholangitis was treated by fasting and intravenous cefoperazone sodium/sulbactam. Antimicrobial agents were used until symptoms associated with cholangitis such as fever and abdominal pain resolved, WBC and CRP were within reference values, and liver enzymes (TB, ALT, and γ-GTP) tended to decrease. No drainage was performed for the bile lake. 1.4. Statistical analyses The predictive ability of the total number of cholangitis cases for the postoperative outcome over 10 years was assessed by area under the receiver operating characteristic (AUROC) curve analyses. The cutoff value was determined based on sensitivity and specificity. The Kaplan–Meier method was used to calculate the NLS. Other statistical analyses were performed using the Mann-Whitney U test for paired comparisons of serial inflammatory parameters between the NLS and LDLT groups. Statistical significance was set at P <0.05. Continuous variables were summarized as medians and ranges. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of the R commander designed to add statistical functions frequently used in biostatistics [6]. 1.5. Ethical approval A retrospective chart review and data collection were performed after obtaining institutional review board approval in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects by the Ministry of Health, Labor, and Welfare of Japan in 2014. This study complied with the 1964 Declaration of Helsinki (revised in 2013). It was approved by the Research Ethics Committee of Kagoshima University Hospital (registration number: 27-133). All participants and their parents provided their informed consent for registration in this study. The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request. Results 2.1. Clinical characteristics The 43 patients were divided into 2 prognostic groups based on their outcomes: the NLS group (n=30, 69.8%) and the LDLT group (n=13, 30.2%). clinical characteristics of the NLS and LDLT groups are shown in Table 1. None of the patients had undergone primary LDLT and deceased donor liver transplant. There were no significant differences in the age at KPE between the two groups. LDLTs were performed at a median age of 1.6 years (range; 0.9-10.4). The follow-up period was significantly longer in the LDLT group than in the NLS group (17.5 vs 11.6 years, p <0.05). Thirteen (30.2%) of the 43 patients had no episodes of cholangitis during the postoperative period, and none of these patients subsequently required LDLT. 2.2. Total episodes of cholangitis and the outcomes Among the 43 patients, 30 (69.8%) experienced 130 episodes of cholangitis (Figure 1). The number of cholangitis episodes per person was significantly higher in the LDLT group than that in the NLS group (4.5 vs 2.4, p <0.05) (Table 1). We analyzed the NLS rate using the AUROC curve of the total number of patients with postoperative cholangitis. In the AUROC curve analysis, the cutoff value of the total number of cholangitis episodes experienced was 3, with an AUROC curve of 0.695 (95% confidence interval: 0.522–0.868) (Figure 2a). This result showed that those who had more than 3 episodes of cholangitis were likely to receive LDLT ( p <0.05) (Figure 2b). 2.3. Comparisons of laboratory data at the time of cholangitis between the NLS and LDLT groups Before 3 years old, 113 episodes (86.9%) of cholangitis were recognized (Figure 3): 19 patients with 71 cholangitis episodes in the NLS group and 10 patients with 42 cholangitis episodes in the LDLT group. Table 2 illustrates the characteristics of laboratory data at the time of cholangitis occurrence before three years old. The NLR in the NLS group was approximately half that in the LDLT group (0.85 vs. 1.63, p <0.001). Similarly, the lymphocyte ratio was significantly higher in the NLS group than in the LDLT group (47.75 vs. 33.30, p <0.001). The TB and γ-GTP levels in the NLS group were significantly lower than those in the LDLT group (1.2 vs. 3.0, p <0.001, 436 vs. 668, p <0.01, respectively). However, there was no marked difference between the groups in the WBC, CRP, or ALT values at the onset of cholangitis. Discussion We investigated the prognostic impact and characteristics of postoperative cholangitis in patients who underwent KPE for BA at our institution over approximately 20 years. The major findings of this study were as follows: (1) among the 43 patients, 30 experienced a total of 130 episodes of cholangitis; (2) those who had more than 3 episodes of cholangitis were more likely to undergo LDLT than those with fewer episodes; (3) cholangitis after KPE occurred before 3 years old in 86.9% of cases; and (4) the NLR at the time of cholangitis in the NLS group was about half that in the LDLT group. Recurrent cholangitis is considered a major prognostic factor affecting the outcomes of KPE for BA. According to a recent national database study in the USA, the median number of cholangitis episodes within two years was two [7]. Similarly, in our series, episodes of cholangitis most frequently occurred before three years old, and patients with more than three episodes of cholangitis were likely to undergo LDLT. Therefore, we focused on short- to mid-term episodes of cholangitis. Multiple studies have revealed that recurrent cholangitis episodes cause progressive liver injury and fibrosis, leading to cirrhosis and liver failure [8-10]. This is likely due to repeated inflammation and cell damage induced by cholangitis spreading from the biliary tree [9,11]. However, the detailed mechanism underlying the frequent incidence of cholangitis in the early postoperative period is unclear. Several possible causes of postoperative cholangitis have been reported [3,2,12]. Cholangitis caused by cholestasis due to obstructive adhesions is a type of cholangitis with a clear and easily understood mechanism. In postoperative patients with good bile excretion who suddenly develop repeated episodes of cholangitis with neutrophilia, it is our clinical experience to rule out stasis in the jejunal limb [13] by hepatobiliary scintigraphy using technetium 99m-N-pyridoxyl-5-methyl tryptophan (PMT) to evaluate the transition of bile through the Roux-en-Y limb to the upper jejunum. If there is abnormal limb retention, adhesiolysis of the limb should be recommended. Our study suggests that cholangitis with neutrophilia is not the only cause of postoperative cholangitis. Cholangitis in the NLS group was lymphocyte-dominant and atypical in its pathogenesis. We propose the term "non-suppurative cholangitis" to describe this pathological entity more accurately. Recognizing the concept of non-suppurative cholangitis seems to provide us with insight into the etiopathogenesis of BA as well as the daily clinical management of cholangitis in BA from a different aspect. Davenport et al. reported that the outcome of BA was predicted by six months post-KPE [14-16] using various immunological biomarkers, including T helper 17 (Th17) and regulatory T (Treg) cells, and serum levels of adhesion molecules. These markers, all of which are accentuated by IL-6, are not always available in daily clinical practice. In our previous report, we showed that CRP and lymphocyte counts were related to the prognosis of BA [17]. In the present study, the NLR was focused on characterizing episodes of postoperative cholangitis in addition to CRP, which is associated with elevation of IL-6. The NLR of the peripheral blood is an ordinary product of ubiquitous biomarkers that underlies the complex pathophysiological processes of systemic inflammation and immune balance and has recently been reported in patients with systemic inflammatory diseases, including cardiovascular diseases, cancer, and liver transplant patients [18-20]. Episodes of non-suppurative cholangitis seem to reflect an activated inflammatory environment in the BA liver, represented by elevated CRP levels, which may also potentially lead to suppurative cholangitis. This concept corresponds to a previous report on cholangitis cases that were refractory to simple antibiotic administration, which noted that clinical improvement was achieved in 60% of patients following high-dose, short-duration intravenous steroid pulse therapy [21]. The more aggressive use of steroids in the early postoperative period might interrupt the latent condition of immune-mediated flare-up, preventing diminution of bile flow, which potentially allows bacterial overgrowth in the bile duct, leading to suppurative cholangitis. Based on this context, our postoperative protocol, in which all patients receive long-term postoperative prophylactic antibiotics, was not effective. In the present study, we demonstrated for the first time that the NLR is involved in the pathogenesis of cholangitis in BA and affects its outcome. A major limitation of our study was that the definitive diagnosis of cholangitis was symptomatic and difficult to differentiate from other viral infections. Although we evaluated episodes of cholangitis, we found that the NLR as a ubiquitous laboratory biomarker could discriminate between the two types of cholangitis and may allow us to modify our management accordingly, such as antibiotics, aggressive corticosteroid therapy, or lysis of adhesion of the Roux-en-Y limb. A prospective study is warranted to investigate lymphocyte dynamics, including regulatory T cells, to support our concept of defining suppurative and non-suppurative cholangitis, as the Th17/Treg ratio is increased in BA, as seen in autoimmune diseases and graft-versus-host disease [15,16]. Declarations Conflicts of interest The authors declare no conflicts of interest in association with the present study. Author Contribution H.T., M.T. and I.S. wrote the manuscript. T.Y., I.Y., O.M., K.C., M.M., and Y.K. prepared tables and figures. M.R., N.A., S.K., O.S., and M.M. reviewed the literature. K.T., K.T., and I.S. provided conceptual advice. All authors have reviewed the manuscript. Acknowledgement We thank Mr. Brian Quinn for his comments and assistance with this manuscript. This study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS: 23K08052, 23K11934, 22K02859, 22K02918, 22K07848, 22K07894, 22K08719, 22K08757, 22K08758, 22K12888, 22K15925, 21H00908, 21K07867, 21K08623, 21K12754), a research grant from The Mother and Child Health Foundation, and a research grant from the Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics. Data Availability The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request. References Ernest van Heurn LW, Saing H, Tam PK (2003) Cholangitis after hepatic portoenterostomy for biliary atresia: a multivariate analysis of risk factors. J Pediatr 142(5):566-571 Luo Y, Zheng S (2008) Current concept about postoperative cholangitis in biliary atresia. World J Pediatr 4(1):14-19 Wu ET, Chen HL, Ni YH, Lee PI, Hsu HY, Lai HS, Chang MH (2001) Bacterial cholangitis in patients with biliary atresia: impact on short-term outcome. Pediatr Surg Int 17(5-6):390-395 Nio M (2017) Japanese Biliary Atresia Registry. Pediatr Surg Int 33(12):1319-1325 Venkat V, Ng VL, Magee JC, Ye W, Hawthorne K, Harpavat S, Molleston JP, Murray KF, Wang KS, Soufi N, Bass LM, Alonso EM, Bezerra JA, Jensen MK, Kamath BM, Loomes KM, Mack CL, Rosenthal P, Shneider BL, Squires RH, Sokol RJ, Karpen SJ, Childhood Liver Disease Research N (2020) Modeling Outcomes in Children With Biliary Atresia With Native Liver After 2 Years of Age. Hepatol Commun 4(12):1824-1834 Kanda Y (2013) Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 48(3):452-458 Chen G, Liu J, Huang Y, Wu Y, Lu X, Dong R, Shen Z, Sun S, Jiang J, Zheng S (2021) Preventive effect of prophylactic intravenous antibiotics against cholangitis in biliary atresia: a randomized controlled trial. Pediatr Surg Int 37(8):1089-1097 Madadi-Sanjani O, Schukfeh N, Uecker M, Eckmann S, Dingemann J, Ure BM, Petersen C, Kuebler JF (2021) The Intestinal Flora at Kasai Procedure in Children with Biliary Atresia Appears Not to Affect Postoperative Cholangitis. Eur J Pediatr Surg 31(1):80-85 Baek SH, Kang JM, Ihn K, Han SJ, Koh H, Ahn JG (2020) The Epidemiology and Etiology of Cholangitis After Kasai Portoenterostomy in Patients With Biliary Atresia. J Pediatr Gastroenterol Nutr 70(2):171-177 Cheng K, Molleston JP, Bennett WE, Jr. (2020) Cholangitis in Patients With Biliary Atresia Receiving Hepatoportoenterostomy: A National Database Study. J Pediatr Gastroenterol Nutr 71(4):452-458 Houben C, Phelan S, Davenport M (2006) Late-presenting cholangitis and Roux loop obstruction after Kasai portoenterostomy for biliary atresia. J Pediatr Surg 41(6):1159-1164 Ecoffey C, Rothman E, Bernard O, Hadchouel M, Valayer J, Alagille D (1987) Bacterial cholangitis after surgery for biliary atresia. J Pediatr 111(6 Pt 1):824-829 Muraji T, Tsugawa C, Nishijima E, Satoh S, Takamizawa S, Ise K, Maekawa T (2002) Surgical management for intractable cholangitis in biliary atresia. J Pediatr Surg 37(12):1713-1715 Narayanaswamy B, Gonde C, Tredger JM, Hussain M, Vergani D, Davenport M (2007) Serial circulating markers of inflammation in biliary atresia--evolution of the post-operative inflammatory process. Hepatology 46(1):180-187 Hill R, Quaglia A, Hussain M, Hadzic N, Mieli-Vergani G, Vergani D, Davenport M (2015) Th-17 cells infiltrate the liver in human biliary atresia and are related to surgical outcome. J Pediatr Surg 50(8):1297-1303 Yang Y, Liu YJ, Tang ST, Yang L, Yang J, Cao GQ, Zhang JH, Wang XX, Mao YZ (2013) Elevated Th17 cells accompanied by decreased regulatory T cells and cytokine environment in infants with biliary atresia. Pediatr Surg Int 29(12):1249-1260 Harumatsu T, Muraji T, Sugita K, Murakami M, Yano K, Onishi S, Yamada K, Yamada W, Matsukubo M, Kawano T, Muto M, Kaji T, Ieiri S (2022) The preoperative lymphocyte ratio and postoperative C-reactive protein are related to the surgical outcome in biliary atresia: an analysis of serial ubiquitous markers of inflammation. Pediatr Surg Int 38(12):1777-1783 Tamhane UU, Aneja S, Montgomery D, Rogers EK, Eagle KA, Gurm HS (2008) Association between admission neutrophil to lymphocyte ratio and outcomes in patients with acute coronary syndrome. Am J Cardiol 102(6):653-657 Meng XY, Guo XG, Wang HQ, Pan ZY, Lu YG, Yu WF (2020) Baseline neutrophil-lymphocyte ratio is associated with survival for infant living donor liver transplantation for biliary atresia. Pediatr Transplant:e13933 Lorente D, Mateo J, Templeton AJ, Zafeiriou Z, Bianchini D, Ferraldeschi R, Bahl A, Shen L, Su Z, Sartor O, de Bono JS (2015) Baseline neutrophil-lymphocyte ratio (NLR) is associated with survival and response to treatment with second-line chemotherapy for advanced prostate cancer independent of baseline steroid use. Ann Oncol 26(4):750-755 Rothenberg SS, Schroter GP, Karrer FM, Lilly JR (1989) Cholangitis after the Kasai operation for biliary atresia. J Pediatr Surg 24(8):729-732 Tables Table 1 Clinical characteristics comparing the NLS group with the LDLT group NLS group LDLT group p- value Total number of patients 30 13 - Number of cholangitis 72 58 - Number of cholangitis per person 2.4 4.5 < 0.05 Age at KPE surgery (days) 58 (52.5 - 72.5) 67 (58.5 - 79.5) 0.14 Age at LDLT (years) - 1.6 (0.9-10.4) - Follow-up period (years) 11.6 (7.8 - 14.4) 17.5 (13.4 - 20.5) < 0.05 NLS, native liver survivor; LDLT, living-donor liver transplant; KPE, Kasai portoenterostomy. Table 2 Comparison of laboratory data at the time of cholangitis before three years old between the two groups NLS group LDLT group p- value WBC 8870 (6255 - 13295) 8700 (5640 - 11910) 0.59 Lymphocyte ratio 47.75 (37.4 - 58.0) 33.30 (22.0 - 43.5) < 0.001 NLR 0.85 (0.48 - 1.53) 1.63 (1.08 - 2.52) < 0.001 CRP (mg/dl) 1.65 (0.39 - 4.66) 1.60 (0.82 - 4.24) 0.43 ALT (IU/l) 93 (59 - 129) 107 (53 - 206) 0.36 TB (mg/dl) 1.2 (0.65 – 2.4) 3.0 (1.6 - 6.2) < 0.001 γ-GTP (IU/l) 436 (113 - 841) 668 (409 - 1274) < 0.01 NLS, native liver survivor; LDLT, living-donor liver transplant; WBC, white blood cell; NLR, neutrophil-lymphocyte ratio; CRP, C-reactive protein; ALT, alanine aminotransferase; TB, total bilirubin; γ-glutamyltranspeptidase, γ-GTP. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 16 Jul, 2024 Read the published version in Pediatric Surgery International → Version 1 posted Editorial decision: Accepted 06 Jul, 2024 Reviews received at journal 06 Jul, 2024 Reviewers agreed at journal 06 Jul, 2024 Reviewers invited by journal 06 Jul, 2024 Editor assigned by journal 06 Jul, 2024 Submission checks completed at journal 06 Jul, 2024 First submitted to journal 05 Jul, 2024 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-4689737","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":323506671,"identity":"73ece7f0-9d89-4e5b-9287-4785bb1c0e1e","order_by":0,"name":"Toshio Harumatsu","email":"","orcid":"","institution":"Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Toshio","middleName":"","lastName":"Harumatsu","suffix":""},{"id":323506672,"identity":"a2b9843f-c80a-4971-ad20-ef0121f83ac4","order_by":1,"name":"Toshihiro Muraji","email":"","orcid":"","institution":"Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Toshihiro","middleName":"","lastName":"Muraji","suffix":""},{"id":323506673,"identity":"2d39c0e0-e6f7-40cc-9a19-60e96df803eb","order_by":2,"name":"Ryuta Masuya","email":"","orcid":"","institution":"University of Miyazaki","correspondingAuthor":false,"prefix":"","firstName":"Ryuta","middleName":"","lastName":"Masuya","suffix":""},{"id":323506679,"identity":"7bd99cea-975d-46d4-b0a7-684e36b60288","order_by":3,"name":"Yudai Tsuruno","email":"","orcid":"","institution":"Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Yudai","middleName":"","lastName":"Tsuruno","suffix":""},{"id":323506682,"identity":"6845483b-5d39-4f91-8b90-52cc1f3ce28d","order_by":4,"name":"Yumiko Iwamoto","email":"","orcid":"","institution":"Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Yumiko","middleName":"","lastName":"Iwamoto","suffix":""},{"id":323506683,"identity":"f7816a8c-1556-42c8-b6d2-9dc655f9df2e","order_by":5,"name":"Masato Ogata","email":"","orcid":"","institution":"Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Masato","middleName":"","lastName":"Ogata","suffix":""},{"id":323506684,"identity":"86601d71-d13e-4a05-bf0a-474b365ca5f4","order_by":6,"name":"Lynne Takada","email":"","orcid":"","institution":"Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Lynne","middleName":"","lastName":"Takada","suffix":""},{"id":323506685,"identity":"0368797d-f06c-4f9f-9a78-ff2e9db37f7c","order_by":7,"name":"Chihiro Kedoin","email":"","orcid":"","institution":"Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Chihiro","middleName":"","lastName":"Kedoin","suffix":""},{"id":323506686,"identity":"77d9009d-0728-48fe-9ebc-66cb311f9436","order_by":8,"name":"Ayaka Nagano","email":"","orcid":"","institution":"Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Ayaka","middleName":"","lastName":"Nagano","suffix":""},{"id":323506687,"identity":"22613d3d-4820-406a-9373-2dc804af72cb","order_by":9,"name":"Masakazu Murakami","email":"","orcid":"","institution":"Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Masakazu","middleName":"","lastName":"Murakami","suffix":""},{"id":323506688,"identity":"1a8bfef1-54f1-4aa1-840d-121ad209da9a","order_by":10,"name":"Koshiro Sugita","email":"","orcid":"","institution":"Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Koshiro","middleName":"","lastName":"Sugita","suffix":""},{"id":323506689,"identity":"e695fcf0-ec00-45a3-8715-9d6525b20450","order_by":11,"name":"Keisuke Yano","email":"","orcid":"","institution":"Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Keisuke","middleName":"","lastName":"Yano","suffix":""},{"id":323506690,"identity":"cf750be1-5429-4d89-95c5-6b027c1287ae","order_by":12,"name":"Shun Onishi","email":"","orcid":"","institution":"Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Shun","middleName":"","lastName":"Onishi","suffix":""},{"id":323506691,"identity":"916588b2-c800-4f41-9a0b-4b37450933fd","order_by":13,"name":"Takafumi Kawano","email":"","orcid":"","institution":"Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Takafumi","middleName":"","lastName":"Kawano","suffix":""},{"id":323506692,"identity":"1fab05ba-97b8-4010-9bd9-6650c2953f96","order_by":14,"name":"Mitsuru Muto","email":"","orcid":"","institution":"Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Mitsuru","middleName":"","lastName":"Muto","suffix":""},{"id":323506693,"identity":"5bdca787-f3f0-41c8-8008-c7100a03be3b","order_by":15,"name":"Tatsuru Kaji","email":"","orcid":"","institution":"Kurume University of School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Tatsuru","middleName":"","lastName":"Kaji","suffix":""},{"id":323506694,"identity":"5ff0eef1-edf0-4b2e-bb1b-a910ee76fb48","order_by":16,"name":"Satoshi Ieiri","email":"data:image/png;base64,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","orcid":"","institution":"Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University","correspondingAuthor":true,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Ieiri","suffix":""}],"badges":[],"createdAt":"2024-07-05 05:18:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4689737/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4689737/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00383-024-05774-1","type":"published","date":"2024-07-16T16:05:12+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62127672,"identity":"fc44c592-cc9d-4a45-b89e-3ec7447e471b","added_by":"auto","created_at":"2024-08-09 14:59:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":202218,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart of the BA patients with cholangitis.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBA, biliary atresia; KPE, Kasai portoenterostomy.\u003c/p\u003e","description":"","filename":"HarumatsuetalFigure1forAAPS2024Issue.png","url":"https://assets-eu.researchsquare.com/files/rs-4689737/v1/ffd221a55f9613e7a74566dd.png"},{"id":62127674,"identity":"6845cada-37d6-4f82-8950-9b0a0c00e737","added_by":"auto","created_at":"2024-08-09 14:59:52","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":253444,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eROC curve of the cholangitis frequency and the native liver survival curve of the two cohorts\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e(a) ROC curve. (b) Native liver survival curve.\u003c/p\u003e\n\u003cp\u003eROC, receiver operating characteristic; AUC, area under the receiver operating characteristic curve.\u003c/p\u003e","description":"","filename":"HarumatsuetalFigure2forAAPS2024Issue.png","url":"https://assets-eu.researchsquare.com/files/rs-4689737/v1/dfc7706ccbc76a2858bfda30.png"},{"id":62128319,"identity":"0973cd55-c319-45cb-a16a-1813f9f13cd1","added_by":"auto","created_at":"2024-08-09 15:07:52","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":116618,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNumber of episodes of cholangitis according to age.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe \"0\" in Age refers to the period from post-KPE surgery to 6 months of age, and \"0.5\" refers to the period from 7 to 11 months of age.\u003c/p\u003e","description":"","filename":"HarumatsuetalFigure3forAAPS2024Issue.png","url":"https://assets-eu.researchsquare.com/files/rs-4689737/v1/85feec962ed1f94b5d4194e6.png"},{"id":62128330,"identity":"66cefec3-5f08-46fe-8522-33ffbde52c31","added_by":"auto","created_at":"2024-08-09 15:07:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":571262,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4689737/v1/49683b98-6001-4e93-9dd6-b0774fba5901.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Inflammation patterns in early postoperative cholangitis predict long-term outcomes in biliary atresia: A potential role of non-suppurative cholangitis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRepeated episodes of cholangitis after Kasai portoenterostomy (KPE) adversely affect the outcome of patients with biliary atresia (BA) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Possible predisposing factors for cholangitis include an insufficient volume of bile flow due to inherent hepato-cholangiopathy of the BA liver, temporary dehydration with reduced bile flow, and infection of the intrahepatic bile ducts due to bacteria ascending via the bilioenteric conduit with or without its obstruction [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePostoperative prophylactic intravenous antibiotic therapy did not decrease the incidence of cholangitis, even when administered for relatively long periods [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Previously adopted cholangitis-preventing surgical procedures, such as exteriorization of the Roux-en-Y limb or anti-reflux valve placement in the limb, have failed to decrease the number of cholangitis episodes [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Thus, the pathogenetic mechanism underlying postoperative cholangitis in BA may not be simple suppurative cholangitis due to ascending bacteria; rather, it may involve a more complex cholangiopathy.\u003c/p\u003e \u003cp\u003eThis study assessed the characteristics of cholangitis in the early postoperative period and their role in the prognosis.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003e1.1. Study population\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe medical records of 43 patients with BA (male: female = 20:23) who underwent KPE at our institution from 2000 to 2020 were reviewed to investigate the relationship between inflammatory biomarkers and outcomes at the onset of cholangitis. Biomarkers included the white blood cell (WBC) count, neutrophil-to-lymphocyte ratio (NLR), lymphocyte ratio (lymphocytes in the total WBC count), and C-reactive protein (CRP), total bilirubin (TB), alanine aminotransferase (ALT), and \u0026gamma;-glutamyl transferase (\u0026gamma;-GTP) levels.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFirst, we focused on the number of cholangitis episodes in each patient in all episodes of cholangitis occurring in the native liver. Then, we focused on the inflammatory biomarkers of cholangitis before three years old.\u0026nbsp;Each parameter\u0026nbsp;at the onset of all episodes of cholangitis was compared between patients with native liver survival (NLS) and living-donor liver transplant (LDLT).\u003cs\u003e\u003c/s\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e1.2. Surgical and postoperative management\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe KPE procedure performed in this series included reconstruction with a long Roux-en-Y jejunal limb (60 cm) following portal dissection. Postoperative management included the administration of ursodeoxycholic acid and methylprednisolone (initial dose: 4 mg/kg/day) starting intravenously on postoperative day (POD) 2 for 5 days, followed by 2 mg/kg/day for 5 days, followed by oral prednisone (2 mg/kg/day) every other day for 2 months.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn addition to this regimen, the patients received sulbactam sodium 80 mg/kg/day intravenously postoperatively. After the initiation of oral intake, the regimen was switched to cefdinir (10 mg/kg/day) to further reduce the risk of post-operative cholangitis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e1.3. Definition and treatment for cholangitis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe focused on inflammatory biomarkers of cholangitis. Cholangitis was defined as a febrile episode with a body temperature of \u0026ge;38 \u0026deg;C without other obvious clinical sources of infection, as well as a combination of clinical findings. Clinical findings included the elevation of direct bilirubin at least \u0026gt;1 mg/dL above the previous baseline and an ALT or \u0026gamma;-GTP level increase to \u0026ge;2 or 1.5 times the upper limit of normal, respectively [5]. Blood culture tests were not included in the results of this study because they were rarely performed in this study period. Cholangitis was treated by fasting and intravenous cefoperazone sodium/sulbactam. Antimicrobial agents were used until symptoms associated with cholangitis such as fever and abdominal pain resolved, WBC and CRP were within reference values, and liver enzymes (TB, ALT, and \u0026gamma;-GTP) tended to decrease. No drainage was performed for the bile lake. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e1.4. Statistical analyses\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe predictive ability of the total number of cholangitis cases for the postoperative outcome over 10 years was assessed by area under the receiver operating characteristic (AUROC) curve analyses. The cutoff value was determined based on sensitivity and specificity. The Kaplan\u0026ndash;Meier method was used to calculate the NLS. Other statistical analyses were performed using the Mann-Whitney U test for paired comparisons of serial inflammatory parameters between the NLS and LDLT groups. Statistical significance was set at P \u0026lt;0.05. Continuous variables were summarized as medians and ranges.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of\u0026nbsp;the R commander designed to add statistical functions frequently used in biostatistics\u0026nbsp;[6].\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e1.5. Ethical approval\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA retrospective chart review and data collection were performed after obtaining institutional review board approval in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects by the Ministry of Health, Labor, and Welfare of Japan in 2014. This study complied with the 1964 Declaration of Helsinki (revised in 2013). It was approved by the Research Ethics Committee of Kagoshima University Hospital (registration number: 27-133). All participants and their parents provided their informed consent for registration in this study. The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003e2.1. Clinical characteristics\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe 43 patients were divided into 2 prognostic groups based on their outcomes: the NLS group (n=30, 69.8%) and the LDLT group (n=13, 30.2%). clinical characteristics of the NLS and LDLT groups are shown in Table 1. None of the patients had undergone primary LDLT and deceased donor liver transplant. There were no significant differences in the age at KPE between the two groups. LDLTs were performed at a median age of 1.6 years (range; 0.9-10.4). The follow-up period was significantly longer in the LDLT group than in the NLS group (17.5 vs 11.6 years, \u003cem\u003ep\u003c/em\u003e \u0026lt;0.05). Thirteen (30.2%) of the 43 patients had no episodes of cholangitis during the postoperative period, and none of these patients subsequently required LDLT. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e2.2. Total episodes of \u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003echolangitis and the outcomes\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 43 patients, 30 (69.8%) experienced 130 episodes of cholangitis (Figure 1). The number of cholangitis episodes per person was significantly higher in the LDLT group than that in the NLS group (4.5 vs 2.4, \u003cem\u003ep\u003c/em\u003e \u0026lt;0.05) (Table 1).\u003cem\u003e \u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe analyzed the NLS rate using the AUROC curve of the total number of patients with postoperative cholangitis. In the AUROC curve analysis, the cutoff value of the total number of cholangitis episodes experienced was 3, with an AUROC curve of 0.695 (95% confidence interval: 0.522\u0026ndash;0.868) (Figure 2a). This result showed that those who had more than 3 episodes of cholangitis were likely to receive LDLT (\u003cem\u003ep \u003c/em\u003e\u0026lt;0.05) (Figure 2b).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e2.3. Comparisons of laboratory data at the time of cholangitis between the NLS and LDLT groups\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBefore 3 years old, 113 episodes (86.9%) of cholangitis were recognized (Figure 3): 19 patients with 71 cholangitis episodes in the NLS group and 10 patients with 42 cholangitis episodes in the LDLT group. Table 2 illustrates the characteristics of laboratory data at the time of cholangitis occurrence before three years old. The NLR in the NLS group was approximately half that in the LDLT group (0.85 vs. 1.63, \u003cem\u003ep\u003c/em\u003e \u0026lt;0.001). Similarly, the lymphocyte ratio was significantly higher in the NLS group than in the LDLT group (47.75 vs. 33.30, \u003cem\u003ep\u003c/em\u003e \u0026lt;0.001). \u003c/p\u003e\n\u003cp\u003eThe TB and \u0026gamma;-GTP levels in the NLS group were significantly lower than those in the LDLT group (1.2 vs. 3.0, \u003cem\u003ep\u003c/em\u003e \u0026lt;0.001, 436 vs. 668, \u003cem\u003ep\u003c/em\u003e \u0026lt;0.01, respectively). However, there was no marked difference between the groups in the WBC, CRP, or ALT values at the onset of cholangitis.\u003cstrong\u003e\u003cbr\u003e \u003c/strong\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe investigated the prognostic impact and characteristics of postoperative cholangitis in patients who underwent KPE for BA at our institution over approximately 20 years. The major findings of this study were as follows: (1) among the 43 patients, 30 experienced a total of 130 episodes of cholangitis;\u0026nbsp;(2)\u0026nbsp;those who had more than 3 episodes of\u0026nbsp;cholangitis\u0026nbsp;were more likely to undergo LDLT than those with fewer episodes; (3)\u0026nbsp;cholangitis after KPE occurred\u0026nbsp;before 3 years old\u0026nbsp;in 86.9% of\u0026nbsp;cases;\u0026nbsp;and (4)\u0026nbsp;the\u0026nbsp;NLR at the time of\u0026nbsp;cholangitis\u0026nbsp;in the NLS group was about half that in the LDLT group.\u003c/p\u003e\n\u003cp\u003eRecurrent cholangitis is considered a major prognostic factor affecting\u0026nbsp;the outcomes of KPE for BA.\u0026nbsp;According to a recent national database study in the USA, the median number of cholangitis episodes within two years was two\u0026nbsp;[7]. Similarly, in our series,\u0026nbsp;episodes of cholangitis most frequently occurred\u0026nbsp;before three years old,\u0026nbsp;and patients with more than three\u0026nbsp;episodes of cholangitis were likely to undergo\u0026nbsp;LDLT. Therefore,\u0026nbsp;we focused on short- to mid-term episodes of cholangitis.\u0026nbsp;Multiple studies have revealed that recurrent cholangitis episodes cause progressive liver injury and fibrosis, leading to cirrhosis and liver failure\u0026nbsp;[8-10]. This is likely due to repeated inflammation and cell damage induced by cholangitis spreading from the biliary tree\u0026nbsp;[9,11]. However, the detailed mechanism underlying the frequent incidence of cholangitis in the early postoperative period is unclear.\u003c/p\u003e\n\u003cp\u003eSeveral possible causes of postoperative cholangitis have been reported\u0026nbsp;[3,2,12]. Cholangitis caused by cholestasis due to obstructive adhesions is a type of cholangitis with a clear and easily understood mechanism.\u0026nbsp;In postoperative patients with good bile excretion who suddenly develop repeated episodes of cholangitis with neutrophilia, it is our clinical experience to rule out stasis in the jejunal limb\u0026nbsp;[13]\u0026nbsp;by hepatobiliary scintigraphy using technetium 99m-N-pyridoxyl-5-methyl tryptophan (PMT) to evaluate\u0026nbsp;the transition of bile through the Roux-en-Y limb to the upper jejunum. If there is abnormal limb\u0026nbsp;retention,\u0026nbsp;adhesiolysis of the limb should be recommended.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur study suggests that cholangitis with neutrophilia is not the only cause of postoperative cholangitis. Cholangitis in the NLS group was lymphocyte-dominant and atypical in its pathogenesis. We propose the term \u0026quot;non-suppurative cholangitis\u0026quot; to describe this pathological entity\u0026nbsp;more accurately.\u0026nbsp;Recognizing the concept of\u0026nbsp;non-suppurative cholangitis\u0026nbsp;seems to provide us with insight into the etiopathogenesis of BA as well as the daily clinical management of cholangitis in BA from a different aspect.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDavenport et al. reported that the outcome of BA was predicted by six months post-KPE\u0026nbsp;[14-16]\u0026nbsp;using various immunological biomarkers, including T helper 17 (Th17) and regulatory T (Treg) cells, and serum levels of adhesion molecules.\u0026nbsp;These markers, all of which are\u0026nbsp;accentuated by IL-6, are not always available in daily clinical practice. In our previous report, we showed that CRP and lymphocyte counts\u0026nbsp;were related to the prognosis of BA\u0026nbsp;[17]. In the present study, the NLR was focused on characterizing episodes of postoperative\u0026nbsp;cholangitis in addition to CRP, which\u0026nbsp;is associated with elevation of IL-6.\u0026nbsp;The NLR of the peripheral blood is an ordinary product of ubiquitous biomarkers that underlies the complex pathophysiological processes of systemic inflammation and immune balance and has recently been reported in patients with systemic inflammatory diseases, including cardiovascular diseases, cancer, and liver transplant patients\u0026nbsp;[18-20].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEpisodes of\u0026nbsp;non-suppurative cholangitis\u0026nbsp;seem to reflect an activated inflammatory environment in the BA liver, represented by elevated CRP levels, which may also potentially lead to\u0026nbsp;suppurative cholangitis.\u0026nbsp;This concept corresponds to a previous report on cholangitis cases that were refractory to simple antibiotic administration, which noted that clinical improvement was achieved in 60% of patients following high-dose, short-duration\u0026nbsp;intravenous steroid pulse therapy\u0026nbsp;[21].\u0026nbsp;The\u0026nbsp;more aggressive use of steroids in the early postoperative period might interrupt the latent condition of immune-mediated flare-up, preventing diminution of bile flow, which potentially allows bacterial overgrowth in the bile duct, leading to\u0026nbsp;suppurative cholangitis. Based on this context,\u0026nbsp;our postoperative protocol,\u0026nbsp;in which\u0026nbsp;all patients receive long-term postoperative prophylactic antibiotics, was not effective.\u003c/p\u003e\n\u003cp\u003eIn the present study, we demonstrated for the first time that the NLR is involved in the pathogenesis of cholangitis in BA and affects its outcome. A major limitation of our study was that the definitive diagnosis of cholangitis was symptomatic and difficult to differentiate from other viral infections. Although we evaluated episodes of cholangitis, we found that the NLR as a ubiquitous laboratory biomarker could discriminate between the two types of cholangitis and may allow us to modify our management accordingly, such as antibiotics, aggressive corticosteroid therapy, or lysis of adhesion of the Roux-en-Y limb. A prospective study is warranted to investigate lymphocyte dynamics, including regulatory T cells, to support our concept of defining suppurative and non-suppurative cholangitis, as the Th17/Treg ratio is increased in BA, as seen in autoimmune diseases and graft-versus-host disease [15,16].\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe authors declare no conflicts of interest in association with the present study.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eH.T., M.T. and I.S. wrote the manuscript. T.Y., I.Y., O.M., K.C., M.M., and Y.K. prepared tables and figures. M.R., N.A., S.K., O.S., and M.M. reviewed the literature. K.T., K.T., and I.S. provided conceptual advice. All authors have reviewed the manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgement\u003c/h2\u003e\n\u003cp\u003eWe thank Mr. Brian Quinn for his comments and assistance with this manuscript. This study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS: 23K08052, 23K11934, 22K02859, 22K02918, 22K07848, 22K07894, 22K08719, 22K08757, 22K08758, 22K12888, 22K15925, 21H00908, 21K07867, 21K08623, 21K12754), a research grant from The Mother and Child Health Foundation, and a research grant from the Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eErnest van Heurn LW, Saing H, Tam PK (2003) Cholangitis after hepatic portoenterostomy for biliary atresia: a multivariate analysis of risk factors. J Pediatr 142(5):566-571\u003c/li\u003e\n\u003cli\u003eLuo Y, Zheng S (2008) Current concept about postoperative cholangitis in biliary atresia. World J Pediatr 4(1):14-19\u003c/li\u003e\n\u003cli\u003eWu ET, Chen HL, Ni YH, Lee PI, Hsu HY, Lai HS, Chang MH (2001) Bacterial cholangitis in patients with biliary atresia: impact on short-term outcome. Pediatr Surg Int 17(5-6):390-395\u003c/li\u003e\n\u003cli\u003eNio M (2017) Japanese Biliary Atresia Registry. Pediatr Surg Int 33(12):1319-1325\u003c/li\u003e\n\u003cli\u003eVenkat V, Ng VL, Magee JC, Ye W, Hawthorne K, Harpavat S, Molleston JP, Murray KF, Wang KS, Soufi N, Bass LM, Alonso EM, Bezerra JA, Jensen MK, Kamath BM, Loomes KM, Mack CL, Rosenthal P, Shneider BL, Squires RH, Sokol RJ, Karpen SJ, Childhood Liver Disease Research N (2020) Modeling Outcomes in Children With Biliary Atresia With Native Liver After 2 Years of Age. Hepatol Commun 4(12):1824-1834\u003c/li\u003e\n\u003cli\u003eKanda Y (2013) Investigation of the freely available easy-to-use software \u0026apos;EZR\u0026apos; for medical statistics. Bone Marrow Transplant 48(3):452-458\u003c/li\u003e\n\u003cli\u003eChen G, Liu J, Huang Y, Wu Y, Lu X, Dong R, Shen Z, Sun S, Jiang J, Zheng S (2021) Preventive effect of prophylactic intravenous antibiotics against cholangitis in biliary atresia: a randomized controlled trial. Pediatr Surg Int 37(8):1089-1097\u003c/li\u003e\n\u003cli\u003eMadadi-Sanjani O, Schukfeh N, Uecker M, Eckmann S, Dingemann J, Ure BM, Petersen C, Kuebler JF (2021) The Intestinal Flora at Kasai Procedure in Children with Biliary Atresia Appears Not to Affect Postoperative Cholangitis. Eur J Pediatr Surg 31(1):80-85\u003c/li\u003e\n\u003cli\u003eBaek SH, Kang JM, Ihn K, Han SJ, Koh H, Ahn JG (2020) The Epidemiology and Etiology of Cholangitis After Kasai Portoenterostomy in Patients With Biliary Atresia. J Pediatr Gastroenterol Nutr 70(2):171-177\u003c/li\u003e\n\u003cli\u003eCheng K, Molleston JP, Bennett WE, Jr. (2020) Cholangitis in Patients With Biliary Atresia Receiving Hepatoportoenterostomy: A National Database Study. J Pediatr Gastroenterol Nutr 71(4):452-458\u003c/li\u003e\n\u003cli\u003eHouben C, Phelan S, Davenport M (2006) Late-presenting cholangitis and Roux loop obstruction after Kasai portoenterostomy for biliary atresia. J Pediatr Surg 41(6):1159-1164\u003c/li\u003e\n\u003cli\u003eEcoffey C, Rothman E, Bernard O, Hadchouel M, Valayer J, Alagille D (1987) Bacterial cholangitis after surgery for biliary atresia. J Pediatr 111(6 Pt 1):824-829\u003c/li\u003e\n\u003cli\u003eMuraji T, Tsugawa C, Nishijima E, Satoh S, Takamizawa S, Ise K, Maekawa T (2002) Surgical management for intractable cholangitis in biliary atresia. J Pediatr Surg 37(12):1713-1715\u003c/li\u003e\n\u003cli\u003eNarayanaswamy B, Gonde C, Tredger JM, Hussain M, Vergani D, Davenport M (2007) Serial circulating markers of inflammation in biliary atresia--evolution of the post-operative inflammatory process. Hepatology 46(1):180-187\u003c/li\u003e\n\u003cli\u003eHill R, Quaglia A, Hussain M, Hadzic N, Mieli-Vergani G, Vergani D, Davenport M (2015) Th-17 cells infiltrate the liver in human biliary atresia and are related to surgical outcome. J Pediatr Surg 50(8):1297-1303\u003c/li\u003e\n\u003cli\u003eYang Y, Liu YJ, Tang ST, Yang L, Yang J, Cao GQ, Zhang JH, Wang XX, Mao YZ (2013) Elevated Th17 cells accompanied by decreased regulatory T cells and cytokine environment in infants with biliary atresia. Pediatr Surg Int 29(12):1249-1260\u003c/li\u003e\n\u003cli\u003eHarumatsu T, Muraji T, Sugita K, Murakami M, Yano K, Onishi S, Yamada K, Yamada W, Matsukubo M, Kawano T, Muto M, Kaji T, Ieiri S (2022) The preoperative lymphocyte ratio and postoperative C-reactive protein are related to the surgical outcome in biliary atresia: an analysis of serial ubiquitous markers of inflammation. Pediatr Surg Int 38(12):1777-1783\u003c/li\u003e\n\u003cli\u003eTamhane UU, Aneja S, Montgomery D, Rogers EK, Eagle KA, Gurm HS (2008) Association between admission neutrophil to lymphocyte ratio and outcomes in patients with acute coronary syndrome. Am J Cardiol 102(6):653-657\u003c/li\u003e\n\u003cli\u003eMeng XY, Guo XG, Wang HQ, Pan ZY, Lu YG, Yu WF (2020) Baseline neutrophil-lymphocyte ratio is associated with survival for infant living donor liver transplantation for biliary atresia. Pediatr Transplant:e13933\u003c/li\u003e\n\u003cli\u003eLorente D, Mateo J, Templeton AJ, Zafeiriou Z, Bianchini D, Ferraldeschi R, Bahl A, Shen L, Su Z, Sartor O, de Bono JS (2015) Baseline neutrophil-lymphocyte ratio (NLR) is associated with survival and response to treatment with second-line chemotherapy for advanced prostate cancer independent of baseline steroid use. Ann Oncol 26(4):750-755\u003c/li\u003e\n\u003cli\u003eRothenberg SS, Schroter GP, Karrer FM, Lilly JR (1989) Cholangitis after the Kasai operation for biliary atresia. J Pediatr Surg 24(8):729-732\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1 \u0026nbsp; \u0026nbsp; \u0026nbsp;Clinical characteristics comparing the NLS group with the LDLT group\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"775\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.75773195876289%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"23.195876288659793%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNLS group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.195876288659793%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLDLT group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.850515463917526%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep-\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003evalue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.75773195876289%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal number of patients\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.195876288659793%\" valign=\"top\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.195876288659793%\" valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.850515463917526%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.75773195876289%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of cholangitis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.195876288659793%\" valign=\"top\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.195876288659793%\" valign=\"top\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.850515463917526%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.75773195876289%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of cholangitis per person\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.195876288659793%\" valign=\"top\"\u003e\n \u003cp\u003e2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.195876288659793%\" valign=\"top\"\u003e\n \u003cp\u003e4.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.850515463917526%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt; 0.05\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.75773195876289%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at KPE surgery (days)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.195876288659793%\" valign=\"top\"\u003e\n \u003cp\u003e58 (52.5 - 72.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.195876288659793%\" valign=\"top\"\u003e\n \u003cp\u003e67 (58.5 - 79.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.850515463917526%\" valign=\"top\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.75773195876289%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cspan style=\"color: rgb(226, 80, 65);\"\u003eAge at LDLT (years)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.195876288659793%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.195876288659793%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(226, 80, 65);\"\u003e1.6 (0.9-10.4)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.850515463917526%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.75773195876289%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up period (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.195876288659793%\" valign=\"top\"\u003e\n \u003cp\u003e11.6 (7.8 - 14.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.195876288659793%\" valign=\"top\"\u003e\n \u003cp\u003e17.5 (13.4 - 20.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.850515463917526%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt; 0.05\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNLS, native liver survivor; LDLT, living-donor liver transplant; KPE, Kasai portoenterostomy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2 Comparison of laboratory data at the time of cholangitis before three years old\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ebetween the two groups\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"775\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.548387096774192%\" colspan=\"2\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"27.483870967741936%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNLS group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.483870967741936%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLDLT group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.483870967741936%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep-\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003evalue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.548387096774192%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eWBC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.483870967741936%\" valign=\"top\"\u003e\n \u003cp\u003e8870 (6255 - 13295)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.483870967741936%\" valign=\"top\"\u003e\n \u003cp\u003e8700 (5640 - 11910)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.483870967741936%\" valign=\"top\"\u003e\n \u003cp\u003e0.59\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.548387096774192%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLymphocyte ratio\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.483870967741936%\" valign=\"top\"\u003e\n \u003cp\u003e47.75\u0026nbsp;(37.4 - 58.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.483870967741936%\" valign=\"top\"\u003e\n \u003cp\u003e33.30\u0026nbsp;(22.0 - 43.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.483870967741936%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt; 0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.548387096774192%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNLR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.483870967741936%\" valign=\"top\"\u003e\n \u003cp\u003e0.85 (0.48 - 1.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.483870967741936%\" valign=\"top\"\u003e\n \u003cp\u003e1.63 (1.08 - 2.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.483870967741936%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt; 0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.242268041237113%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCRP\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.402061855670103%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e(mg/dl)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.448453608247423%\" valign=\"top\"\u003e\n \u003cp\u003e1.65 (0.39 - 4.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.448453608247423%\" valign=\"top\"\u003e\n \u003cp\u003e1.60 (0.82 - 4.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.45876288659794%\" valign=\"top\"\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.242268041237113%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eALT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.402061855670103%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e(IU/l)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.448453608247423%\" valign=\"top\"\u003e\n \u003cp\u003e93 (59 - 129)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.448453608247423%\" valign=\"top\"\u003e\n \u003cp\u003e107 (53 - 206)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.45876288659794%\" valign=\"top\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.242268041237113%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTB\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.402061855670103%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e(mg/dl)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.448453608247423%\" valign=\"top\"\u003e\n \u003cp\u003e1.2 (0.65 \u0026ndash; 2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.448453608247423%\" valign=\"top\"\u003e\n \u003cp\u003e3.0 (1.6 - 6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.45876288659794%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt; 0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"12.242268041237113%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026gamma;-GTP\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.402061855670103%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e(IU/l)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.448453608247423%\" valign=\"top\"\u003e\n \u003cp\u003e436 (113 - 841)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.448453608247423%\" valign=\"top\"\u003e\n \u003cp\u003e668 (409 - 1274)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.45876288659794%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt; 0.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNLS, native liver survivor; LDLT, living-donor liver transplant; WBC, white blood cell;\u003c/p\u003e\n\u003cp\u003eNLR,\u0026nbsp;neutrophil-lymphocyte ratio; CRP,\u0026nbsp;C-reactive protein;\u0026nbsp;ALT, alanine aminotransferase; TB, total bilirubin;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026gamma;-glutamyltranspeptidase, \u0026gamma;-GTP.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-surgery-international","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pesi","sideBox":"Learn more about [Pediatric Surgery International](http://link.springer.com/journal/383)","snPcode":"383","submissionUrl":"https://submission.nature.com/new-submission/383/3","title":"Pediatric Surgery International","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"biliary atresia, cholangitis, C-reactive protein, neutrophil-lymphocyte ratio, native liver survival rate, Kasai portoenterostomy","lastPublishedDoi":"10.21203/rs.3.rs-4689737/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4689737/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eFrequent postoperative cholangitis in biliary atresia (BA) affects the long-term native liver survival. This study assessed the characteristics of early cholangitis and their influence on the prognosis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eForty-three patients with BA who underwent surgery between 2000 and 2020 were analyzed for routine inflammatory markers. Early cholangitis characteristics were compared between native liver survivor (NLS) and living donor liver transplant (LDLT) patients.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong the 43 patients, 30 (69.8%) experienced 130 episodes of cholangitis. In the area under the receiver operating characteristics curve (AUROC) analysis, the cutoff value of the total cholangitis episodes was 3, with an area under the AUROC curve of 0.695 (95% confidence interval: 0.522\u0026ndash;0.868). Before 3 years old, 113 episodes (86.9%) of cholangitis were observed. The white blood cell, C-reactive protein, and alanine aminotransferase values at cholangitis onset did not markedly differ between the LDLT and NLS groups. Conversely, the neutrophil-to-lymphocyte ratio in the NLS group was significantly lower than in the LDLT group (0.85 vs. 1.63, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eCholangitis in the NLS group was lymphocyte-dominant and atypical in its pathogenesis. Lymphocyte-dominant cholangitis is non-suppurative, and future research should clarify its pathogenesis to improve the treatment and prognosis of BA.\u003c/p\u003e","manuscriptTitle":"Inflammation patterns in early postoperative cholangitis predict long-term outcomes in biliary atresia: A potential role of non-suppurative cholangitis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-09 14:59:47","doi":"10.21203/rs.3.rs-4689737/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2024-07-06T14:04:22+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-06T13:58:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"340165079514415562491512844803786995236","date":"2024-07-06T13:56:57+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-06T11:47:40+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-06T11:47:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-06T07:18:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Surgery International","date":"2024-07-05T05:16:41+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-surgery-international","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pesi","sideBox":"Learn more about [Pediatric Surgery International](http://link.springer.com/journal/383)","snPcode":"383","submissionUrl":"https://submission.nature.com/new-submission/383/3","title":"Pediatric Surgery International","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"69b337b1-eb5a-49e4-b6a0-7405a85544ef","owner":[],"postedDate":"August 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-09T14:59:47+00:00","versionOfRecord":{"articleIdentity":"rs-4689737","link":"https://doi.org/10.1007/s00383-024-05774-1","journal":{"identity":"pediatric-surgery-international","isVorOnly":false,"title":"Pediatric Surgery International"},"publishedOn":"2024-07-16 16:05:12","publishedOnDateReadable":"July 16th, 2024"},"versionCreatedAt":"2024-08-09 14:59:47","video":"","vorDoi":"10.1007/s00383-024-05774-1","vorDoiUrl":"https://doi.org/10.1007/s00383-024-05774-1","workflowStages":[]},"version":"v1","identity":"rs-4689737","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4689737","identity":"rs-4689737","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}