Journal of Pediatric Gastroenterology and Nutrition, Publish Ahead of Print DOI : 10.1097/MPG.0000000000002836 Cholangitis in Patients with Biliary Atresia Receiving Hepatoportoenterostomy: A National Database Study Katherine Cheng, M.D.1 Jean P. Molleston, M.D.2 William E. Bennett, Jr., M.D., M.S.2,3 1. Department of Pediatrics, 2. Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 3. Section of Pediatric and Adolescent Comparative Effectiveness Research, Indiana University School of Medicine, Indianapolis, IN, USA Abstract: Introduction: Biliary atresia (BA) is a progressive form of liver disease in the neonatal period usually requiring hepatoportoenterostomy (HPE). Cholangitis is a common sequelae of HPE, but data about which patients are at risk for this complication are limited. Objective: To determine risk factors associated with cholangitis in a large retrospective cohort after HPE. Methods: The Pediatric Health Information System (PHIS) was queried for BA (ICD-9 975.61) and HPE (ICD-9-CM 51.37) admissions from 2004-2013. We performed univariate Copyright © ESPGHAN and NASPGHAN. All rights reserved. analysis and linear regression with dependent variables of ≥ 2 or ≥ 5 episodes of cholangitis, and independent variables of age at time of HPE, race, ethnicity, gender, insurance, ursodeoxycholic acid (UDCA) use, steroid use, presence of esophageal varices (EV), and portal hypertension (PH). Results: We identified 1,112 subjects with a median age at HPE of 63 days and median number of cholangitis episodes of 2 within 2 years. On multiple regression analysis, black race (OR 1.51, p = 0.044) and presence of PH (OR 2.24, p < 0.001) were associated with increased risk of ≥ 2 episodes of cholangitis, while HPE at > 90 days was associated with less risk (OR 0.46, p = 0.001). Among those with ≥ 5 episodes, Asian race (OR 2.66, p= 0.038), public insurance (OR 1.72, p = 0.043), EV (OR 1.81, p = 0.017), and PH (OR 2.88, p <0.001) were associated with higher risk. Conclusion: Complications such as cholangitis remain a common problem for patients, after HPE, with median of 2 episodes within 2 years. Higher rates of cholangitis are associated with portal hypertension while lower rate is associated with age at HPE of > 90 days. Asians, patients with public insurance, and those with portal hypertension are more likely to have recurrent cholangitis. Keywords: portal hypertension; liver disease What is known: Hepatoportoenterostomy (HPE) performed at age < 60 days is associated with improved patient outcomes in BA. Cholangitis is a common complication in patients with biliary atresia after HPE What is new: The presence of portal hypertension and black race is associated with a higher risk of cholangitis after HPE. The use of corticosteroids and ursodeoxycholic acid are not associated with lower risk of cholangitis. The frequency of cholangitis episodes after HPE may be under-recognized in the literature. Copyright © ESPGHAN and NASPGHAN. All rights reserved. INTRODUCTION Biliary atresia (BA) is a progressive form of liver disease that presents in the neonatal period and affects about 1/12,000 live births in the United States.[1] As the most common cause of extrahepatic obstructive jaundice and end stage liver disease in infants, it is also the leading indication for liver transplant in children.. The etiology of BA is unknown, but many theories hypothesize that viral infections, autoimmune mediated destruction, genetic mutation, and toxins may underlie this disease.[2-5] After diagnosis, patients are generally referred for hepatoportoenterostomy (HPE). The success of this procedure is often measured by normalization of the bilirubin level, yet previous national registry studies showed that this is only achieved in 39-57%. [6-8] Multiple factors can affect the success of the procedure[9, 10] including anatomy of the biliary remnant,[11] presence of cirrhosis at time of surgery,[12, 13] portal pressure at time of procedure, associated malformations,[14, 15] age at the time of HPE, surgical experience of treatment center,[6, 11, 16] and postoperative complications.[17] Current therapies after HPE aim to prevent complications such as cholangitis, growth failure, malnutrition, and portal hypertension.[9] Regardless of the adjunctive therapy employed, the direct communication between intestine and bile ducts created by HPE confers a higher risk of ascending cholangitis. Notably, 40-60% of infants develop cholangitis in the first two years after HPE.[15] Some treatment centers have adopted the use of prophylactic oral antibiotics to decrease rates of cholangitis.[18] Liver transplant is indicated when HPE fails to restore biliary drainage or when complications such as cirrhosis occur. Previous research found that 40% of patients underwent liver transplant by two years of age,[15] and more than 70% of patients ultimately required transplant before adulthood.[19] Copyright © ESPGHAN and NASPGHAN. All rights reserved. We hypothesized that additional demographic and clinical factors may be associated with higher or lower rates of cholangitis. We performed a retrospective cohort analysis of children undergoing HPE in a large administrative database of American children’s hospitals, and assessed the associations between patient demographics and clinical features and the rate of admissions for cholangitis. METHODS Data for this study were obtained from the Pediatric Health Information System (PHIS), an administrative database that contains inpatient, emergency department, ambulatory surgery and observation encounter-level data from 48 not-for-profit, tertiary care pediatric hospitals in the United States. These hospitals are affiliated with the Children’s Hospital Association (Lenexa, KS). Data quality and reliability are assured through a joint effort between the Children’s Hospital Association and participating hospitals. Portions of the data submission and data quality processes for the PHIS database are managed by Truven Health Analytics (Ann Arbor, MI). For the purposes of external benchmarking, participating hospitals provide discharge/encounter data including demographics, diagnoses, and procedures. Nearly all of these hospitals also submit resource utilization data (e.g. pharmaceuticals, imaging, and laboratory) into PHIS. Data are de-identified at the time of data submission, and data are subjected to a number of reliability and validity checks before being included in the database. For this study, data from 48 hospitals was included. We included all subjects who were admitted between 2004 and 2013 using ICD-9 diagnosis codes for both biliary atresia (751.61) and hepatoportoenterostomy (51.37) and age < 9 months at the time of HPE. Patients older than 9 months were excluded from this analysis due to the small incidence of BA and resultant HPE in this age group (thus concern this may represent other operations or patients who did not have BA). We also determined the Copyright © ESPGHAN and NASPGHAN. All rights reserved. following variables for each subject: age at time of HPE, gender, race, ethnicity, insurance type, date and year of HPE, hospital site, and transplant date (if present). For the purposes of analysis by hospital HPE experience, we sorted hospitals by the average number of HPEs performed per year and divided them evenly into three tiers. Hospitals were deemed A) high volume for > 3, B) medium volume for 1-3, and C) low volume for <1 HPEs per year on average. Data were gathered from patients throughout the whole study period of 2004-2013 to identify the presence of complications of BA (portal hypertension, esophageal varices) or cholangitis, as well as the use of ursodeoxycholic acid or steroids at the time of discharge after HPE. Cholangitis was identified by ICD-9 diagnosis code 576.1, esophageal varices by a diagnostic code 456.0 and or a procedure code for variceal treatment (42.91 or 42.33). Portal hypertension was identified by ICD-9 diagnosis code of 572.3, as well as associated procedures/complications such as ascites (789.5 and 789.59), and paracentesis (ICD 9-CM 54.91). Statistical Analysis We first performed chi square univariate analysis between each demographic variable and the presence or absence of ≥ 2 episodes and ≥ 5 episodes of cholangitis. We specifically determined examined patient demographics in general as well as risk of cholangitis with respect to age at time of HPE, gender, race, ethnicity, insurance type, hospital HPE volume, UDCA use, steroid use, presence of esophageal varices or portal hypertension. We then performed logistic regression analysis with mixed effects (hospital was modeled as a random effect, the remainder as fixed effects). For the multiple regression, we built two models, using the dependent variables of the presence of ≥2 or ≥5 episodes of cholangitis. Independent variables include race, ethnicity, gender, time of HPE, insurance, UDCA use, steroid use, and Copyright © ESPGHAN and NASPGHAN. All rights reserved. presence of esophageal varices or portal hypertension. Hospital site was modeled as a random effect to account for variation in practice among institutions. Statistical significance was determined at p < 0.05. We also ran the same regression model with the exception of having esophageal varices and portal hypertension as an interactive term. The goodness of fit between these models was similar, so we defaulted to the simpler model that included all variables as independent variables.