Copyright © ESPGHAN and NASPGHAN. All Rights Reserved

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.

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.

Finally, we performed a survival analysis for the entire study period, with times since HPE plotted against the proportion of patients with cholangitis-free survival. Subgroups were compared using the log rank test.

Models were built using the R software package (http://www.r-project.org) and the lme4 library for generalized linear / logistic models (http://cran.r-project.org/package=lme4/).

This study was approved by the Indiana University Institutional Review Board as an exempt study.

RESULTS

Cohort characteristics

We identified 1,112 subjects from the PHIS database who met inclusion criteria (Table 1).

59.5% were female, 676 (60.8%) were white, 163 (14.7%) were black, 51 were Asian (4.6%), and 222 (19.9%) were classified as either other or unknown race. The median age of HPE was 63 days with an interquartile range of 32 days. 44.7% of patients received HPE prior to

60 days of life. 933 patients (83.9%) had HPE at centers that also perform liver transplant.

365 (32.8%) patients underwent transplant after HPE during the study period.

After HPE, the mean reported number of cholangitis episodes per subject was 1.82 during at least 2 years of follow up. Notably, 440 (39.6%) patients did not have any episodes of cholangitis, and 414 (37.2%) reported 2 or more episodes of cholangitis. 173 patients had esophageal varices, while 624 patients had portal hypertension.

Univariate Analysis

Table 2 shows that subjects were less likely to have ≥2 episodes of cholangitis if they were

Hispanic (OR 0.678, p = 0.019), underwent HPE at ≤ 45 days of life (OR 0.361, p < 0.001), or had commercial insurance (OR 0.688, p = 0.004). On the contrary, patients were more likely to report ≥2 episodes of cholangitis if they were non-Hispanic (OR 1.48, p = 0.002), or underwent HPE at 60-90 (OR 1.90, p < 0.001) or >90 days of life (OR 1.41, p = 0.043), have public insurance (OR 1.31, p = 0.032), esophageal varices (OR 1.52, p = 0.013), or portal hypertension (OR 1.91, p < 0.001). Race, gender, hospital volume, UDCA use, steroid use, and HPE at transplant center were not associated with an increased or diminished risk of cholangitis.

Logistic Regression

We then performed linear regression analysis with mixed effects (Table 3). Several associations were demonstrated when this more complex model was used. First, HPE at age greater than 90 days was associated with lower risk of reported cholangitis (OR 0.46, p =

0.001). Black race (OR 1.51, p = 0.044) and portal hypertension (OR 2.24, p < 0. 001) were associated with higher risk of cholangitis. Ethnicity, gender, insurance type, UDCA use, steroid use, and presence of esophageal varices were not shown to have significant

There were 119 patients (10.7%) who reported five or more episodes of cholangitis during the study period. Using the same variables, we ran linear regression analysis on this cohort as well (Table 4). In this cohort, we found non-Hispanics (OR 0.52, p = 0.023) were less likely to have frequent episodes of cholangitis. Asians (OR 2.66, p = 0.038), patients with public insurance (OR 1.72, p = 0.043), esophageal varices (OR 1.81, p = 0.017) or portal hypertension (OR 2.88, p < 0.001) were associated with increased risk of cholangitis. Age at time of HPE and gender were not associated with risk of frequent cholangitis.

Survival Analysis

Survival curves are shown in Figure 1. 1102 subjects had sufficient data (encounters in PHIS beyond 2 years from initial HPE) for survival analysis. When stratified by clinical features

(esophageal varices, portal HTN, neither of these, or both of these), those with neither had significantly higher cholangitis-free survival overall when compared to both, varices, or portal HTN (p < 0.001). This significance was not present after 2 years (p = 0.843), but was present after 5 (p = 0.008), or 10 (p <0.001) years post-HPE. There were no significant differences at any time point (or overall) among those with both, varices only, or portal HTN only.

DISCUSSION

This study describes 1,112 infants with biliary atresia who were surgically managed with

HPE between 2004 and 2013 at 48 centers participating in the PHIS database. We found that higher rates of cholangitis were associated with portal hypertension and black race, and frequency was decreased in subjects who had HPE after 90 days of life. Furthermore,

BA is not typically evident until between two to six weeks of life with persistent jaundice, acholic stools, dark urine, and/or hepatomegaly.[20] Physicians must maintain a high level of clinical suspicion for BA because early signs of the disease are often subtle. Early HPE is considered the standard of treatment. Importantly, previous studies have demonstrated that timely identification of BA and subsequent HPE prior to 60 days of life is associated with better outcomes. [11] Intervention at an even earlier age (<45 days) has been linked to better patient outcomes and a longer native liver survival period.[10] In spite of these studies, the average age at time of HPE has actually increased from 61 days of life based on a population study published in 2006[15] versus 63 days found in this study. 55% of patients underwent

HPE after 60 days of life in our study.

Cholangitis is a common complication for patients after HPE and it is often diagnosed based on fever without any other clear source, symptoms such as jaundice, new onset of acholic stool, or right upper quadrant pain and tenderness and elevation of serum bilirubin level.[21]

Most episodes occur within the first two years after HPE[22] but some can occur even twenty years after initial surgery.[23] A limitation in this study is the lack of clear definition for cholangitis diagnosis because it relies on ICD9 coding but we report 60.4% of patients to have one or more episodes of cholangitis within 2 years of HPE, which is similar to a previous report by Ng and colleagues (62%).[21] However, our study demonstrated a higher percentage of patients with multiple episodes of cholangitis(37% of our cohort vs. 5% in

Ng’s study). This suggests that the frequency of cholangitis after HPE may be underestimated. This is significant as previous researchers have found that repeated episodes of cholangitis are associated with poor outcomes and native liver survival.[17, 22, 24]

Despite these findings, there have been no previous studies to determine the association between patient demographics and the likelihood of cholangitis. In our study, mixed effects regression demonstrated that patients who had HPE after 90 days of life actually had a significantly lower risk of having two or more episodes of cholangitis. This may be explained by the prevailing notion that infants who have HPE at an earlier age typically have better biliary drainage, which allows for easier communication between the intestines and bile ducts, thereby increasing the risk of ascending cholangitis.[15] Based on these results, the risk of cholangitis and its relationship to timing of HPE are likely complex.

Portal hypertension is another common complication after HPE and can lead to significant morbidity and mortality.[26] Duche et al showed that 50% of infants already have elevated portal pressures at the time of HPE and this correlates with poor native liver survival.[14]

Since BA is a progressive disease, the complications of portal hypertension such as variceal bleeding and ascites continue to worsen with time and need to be monitored and managed accordingly. Prevalence of portal hypertension may also be underestimated in previous studies because there is no simple measurement of portal pressure. Elevated pressure typically precedes the development of both varices and ascites. Shneider et al used data from the Biliary Atresia Study of Infants and Children (BASIC) study and found that 24% of patients develop ascites and 8% develop varices in the 24 month period after undergoing

HPE.[15] In our study, we found that 56% of patients had portal hypertension and 15.6% had esophageal varices reported over time. The number of patients with portal hypertension in our study may be underestimated because patients reporting esophageal varices may not have also reported portal hypertension. Despite this, both univariate and logistic regression demonstrated an association between portal hypertension and higher likelihood of

Copyright © ESPGHAN and NASPGHAN. All rights reserved. cholangitis. Based on cholangitis-free survival curve (figure 1), the presence of portal hypertension and/or esophageal was associated with earlier cholangitis episode, potentially due to worsen immune system as liver disease progresses.

Several treatments we commonly use in patients with BA after HPE such as UDCA and steroids were found to have no significant impact on patient outcome. UDCA has been shown to improve bile flow in various cholestatic diseases[27] and previous studies in patients with biliary atresia demonstrated that the use of UDCA can lead to reduced bilirubin level, improve nutritional status and clinical symptoms but does not improve survival time or need for liver transplant.[28-31] A study by Kotb on 141 infants with biliary atresia after HPE did not demonstrate improvement in outcome but rather longer duration to resolution of cholestasis, and more hepatic and extrahepatic complications associated with UDCA.[32] In our study, the use of UDCA was not shown to have significant positive impact on risk of cholangitis. There remains a question of whether the use of UDCA is effective in patients with biliary atresia after HPE and a large prospective multi-center study is needed.

Corticosteroids were thought to provide anti-inflammatory and immunomodulatory effects.

The Steroids in Biliary Atresia Randomized Trial (START) did not find any statically significant improvement in bile drainage or transplant-free survival rate at six months between the placebo and high dose steroids after HPE.[33] START trial also demonstrated slow growth trajectories and earlier development of serious adverse event with steroid use compared to placebo. [33, 34]Similar to the START trial, the patients in our study who used corticosteroids after HPE (55%) also failed to demonstrate a decreased association with risk of cholangitis in both univariate and multivariate models. One potential cofounding factor for using this dataset is the lack of information on detailed dosing history, as well medication adherence. Due to the type of administrative data we used, we were unable to analyze the effect of prophylactic antibiotics use on cholangitis development. Our dataset provided

Copyright © ESPGHAN and NASPGHAN. All rights reserved. information about antibiotics at time of discharge but we are unable to estimate the number of patients who were placed on them for prophylactic or treatment use.

This study did not demonstrate any statistically significant distinction between ethnicity, gender and insurance type when patients with <2 episodes of cholangitis are compared to those with ≥2. However, subgroup analysis of recurrent cholangitis (those with 5 or more episodes) demonstrated an association with Asian race. Non- Hispanics were less likely to have recurrent cholangitis. While we found higher percentage of patients with multiple episodes of cholangitis (37%) compared to previous U.S. study, our value is actually similar to previous studies in Taiwan (22%) and Hong Kong (25%). [17, 24] This suggests that there may be a genetic component to frequent recurrence of ascending infection, although it is difficult to assess from this study alone. Insurance type may be a surrogate measure of socioeconomic status, and public insurance is also shown to be an increased risk for recurrent cholangitis.

The most significant limitation of this study is its ability to capture all post-HPE cholangitis episodes, since patients may have been treated at hospitals outside of the PHIS system during follow up; however, the hospitals in the PHIS system includes the majority of all tertiary referral pediatric hospitals in the U.S., which are the typical referral sites for patients with biliary atresia. Still, we are likely to have underestimated the total burden of cholangitis since an unknown number of follow-up encounters were uncounted, and we only performed our primary analysis on cholangitis within 2 years (other than the survival analysis).

Additionally, we may have undercounted our initial cohort, since patients that had HPE at another institution or between institutions would not have been included. We attempted to account for this by only including patients with an HPE performed in PHIS hospitals in our study. This study also lacks information on outpatient cholangitis treatment or prophylactic antibiotics as mentioned above, which has been used by some treatment centers to prevent

Future studies should focus on prospective analysis of the factors that may mediate risk for cholestasis. Based on our study, the focus should be on risk stratification by demographics

(especially age at HPE and race) and clinical factors such as the presence of portal HTN and esophageal varices.

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Gender, n (%)

Male 450 (40.5)

Female 662 (59.5)

Age at time of HPE, n (%)

Median age in days 63

≤ 45 275 (24.7)

46-59 224 (20.1)

60-90 448 (40.3)

> 90 165 (14.8)

Race, n (%)

White 676 (60.8)

Black 163 (14.7)

Asian 51 (4.6)

Other 164 (14.7)

Unknown 58 (5.2)

Ethnicity, n (%)

Hispanics 206 (18.5)

Non-Hispanics 494 (44.4)

Unknown 412 (37.1)

Insurance, n (%)

Commercial 406 (36.5)

Public 558 (50.2)

Other 143 (12.9)

Unknown 5 (0.4)

Steroid use, n (%) 611 (54.9)

UDCA use, n (%) 877 (78.9)

HPE at transplant center, n (%) 933 (83.9)

Average Number of Cholangitis 1.82

≥2 episodes of Cholangitis 414 (37.2%)

≥5 episodes of Cholangitis 119 (10.7%)

Tota < 2 ≥2 Odds P- 95% CI l Cholangitis cholangitis Ratio value

Race

White 676 421 (62.3) 255 (37.7) 1.055 0.822-1.354 0.673

Black 163 97 (59.5) 66 (40.5) 1.175 0.837-1.650 0.351

Asian 51 32 (62.7) 19 (37.3) 1.001 0.560-1.790 0.997

Other 164 110 (67.1) 54 (32.9) 0.802 0.564-1.139 0.217

Unknown 58 38 (65.5) 20 (34.5) 0.882 0.506-1.537 0.657

Ethnicity

Hispanics 206 144 (69.9) 62 (30.1) 0.678 0.489-0.939 0.019

Non-Hispanics 494 285 (57.7) 209 (42.3) 1.477 1.157-1.887 0.002

Unknown 412 269 (65.3) 143 (34.7) 0.842 0.653-1.084 0.182

Gender

Female 662 421 (63.6) 241 (36.4) 0.917 0.716-1.174 0.49

Male 450 277 (61.6) 173 (38.4) 1.091 0.852-1.397 0.49

Age at HPE

≤45 days 275 217 (78.9) 58 (21.1) 0.361 0.262-0.498 <0.001

46-59 224 148 (66.1) 76 (33.9) 0.836 0.614-1.137 0.253

60-90 448 241 (53.8) 207 (46.2) 1.896 1.48-2.430 <0.001

>90 165 92 (55.8) 73 (44.2) 1.41 1.009-1.971 0.043

Insurance

Commercial 406 277 (68.2) 129 (31.8) 0.688 0.532-0.890 0.004

Other 143 87 (60.8) 56 (39.2) 1.099 0.766-1.575 0.609

0.757- Unknown 5 1 (20.0) 4 (80.0) 6.8 0.047 61.046

Hospital Volume

High 695 436 (62.7) 259 (37.3) 1.004 0.781-1.291 0.974

Medium 372 233 (62.6) 139 (37.4) 1.009 0.780-1.305 0.947

Low 45 29 (64.4) 16 (35.6) 0.927 0.497-1.729 0.812

UDCA 877 542 (61.8) 335 (38.2) 1.221 0.901-1.652 0.197

Steroids 611 374 (61.2) 237 (38.8) 1.16 0.908-1.482 0.235

Transplant 365 226 (61.9) 139 (38.1) 1.056 0.815-1.367 0.681

HPE at transplant 933 583 (62.5) 350 (37.5) 1.079 0.773-1.505 0.656 center

EV 173 94 (54.3) 79 (45.7) 1.515 1.092-2.103 0.013

Portal HTN 624 351 (56.3) 273 (43.8) 1.914 1.488-2.462 <0.001

Odds ratio 95% CI p value

Race

White - - -

Black 1.51 1.01-2.25 0.044

Asian 1.55 0.82-2.94 0.175

Other 1.13 0.77-1.66 0.534

Unknown 0.66 0.35-1.24 0.198

Ethnicity

Hispanic - - -

Non-Hispanic 0.81 0.55-1.19 0.278

Unknown 1.03 0.68-1.54 0.902

Gender

Female - - -

Male 1.12 0.86-1.45 0.4

Age at HPE

≤45 days - - -

46-59 0.78 0.53-1.16 0.221

60-90 0.96 0.69-1.34 0.811

> 90 0.46 0.29-0.72 0.001

Insurance

Public 1.27 0.93-1.73 0.137

Other 1.28 0.83-1.99 0.265

Unknown 9.43 0.88-100.65 0.063

UDCA Use 1.07 0.76-1.5 0.71

Steroid use 1.19 0.89-1.59 0.231

EV 1.13 0.78-1.63 0.521

Portal HTN 2.24 1.67-3 <0.001

Odds ratio 95% CI p value

Race

White - - -

Black 1.2 0.63-2.3 0.584

Asian 2.66 1.06-6.66 0.038

Other 1.44 0.82-2.51 0.2

Unknown 0.86 0.31-2.4 0.776

Ethnicity

Hispanic - - -

Non-Hispanic 0.52 0.3-0.91 0.023

Unknown 0.59 0.33-1.06 0.076

Gender

Female - - -

Male 1.25 0.83-1.88 0.282

Age at HPE

≤45 days - - -

46-59 1.06 0.57-1.96 0.853

60-90 0.77 0.45-1.33 0.35

> 90 0.7 0.35-1.41 0.321

Insurance

Public 1.72 1.02-2.91 0.043

Other 1.92 0.97-3.81 0.062

Unknown 0 0-infinity 0.988

UDCA Use 0.89 0.53-1.5 0.661

Steroid use 0.91 0.58-1.42 0.671

EV 1.81 1.11-2.96 0.017

Portal HTN 2.88 1.73-4.82 0