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Table 1.  
Demographic Characteristicsa
Demographic Characteristicsa
Table 2.  
Risk Factors for ARP vs CP in Childrena
Risk Factors for ARP vs CP in Childrena
Table 3.  
Disease Burden of ARP or CP in Childrena
Disease Burden of ARP or CP in Childrena
Table 4.  
Imaging Findings in ARP and CP in Childrena
Imaging Findings in ARP and CP in Childrena
Table 5.  
Treatments for ARP and CP in Childrena
Treatments for ARP and CP in Childrena
1.
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Lee  YJ, Kim  KM, Choi  JH, Lee  BH, Kim  GH, Yoo  HW.  High incidence of PRSS1 and SPINK1 mutations in Korean children with acute recurrent and chronic pancreatitis.  J Pediatr Gastroenterol Nutr. 2011;52(4):478-481.PubMedArticle
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Derikx  MH, Kovacs  P, Scholz  M,  et al; PanEuropean Working Group on Alcoholic Chronic Pancreatitis Members and Collaborators.  Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study.  Gut. 2015;64(9):1426-1433.PubMedArticle
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Original Investigation
June 2016

Risk Factors Associated With Pediatric Acute Recurrent and Chronic PancreatitisLessons From INSPPIRE

Author Affiliations
  • 1Nationwide Children’s Hospital, Columbus, Ohio
  • 2University of New South Wales, Sydney Children’s Hospital Randwick, Sydney, Australia
  • 3Medical College of Wisconsin, Milwaukee
  • 4Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
  • 5University of Texas Southwestern Medical School, Dallas
  • 6University of Minnesota Masonic Children’s Hospital, Minneapolis
  • 7Hospital for Sick Children, Toronto, Ontario, Canada
  • 8Baylor College of Medicine, Houston, Texas
  • 9Harvard Medical School, Boston, Massachusetts
  • 10Seattle Children’s Hospital, Seattle, Washington
  • 11University of California, San Francisco
  • 12Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
  • 13Montreal Children’s Hospital, McGill University, Montreal, Quebec, Canada
  • 14University of Utah, Salt Lake City
  • 15Hadassah Hebrew University Hospital, Jerusalem, Israel
  • 16University of Iowa Children’s Hospital, Iowa City
JAMA Pediatr. 2016;170(6):562-569. doi:10.1001/jamapediatrics.2015.4955
Abstract

Importance  Pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) are poorly understood.

Objective  To characterize and identify risk factors associated with ARP and CP in childhood.

Design, Setting, and Participants  A multinational cross-sectional study of children with ARP or CP at the time of enrollment to the INSPPIRE (International Study Group of Pediatric Pancreatitis: In Search for a Cure) study at participant institutions of the INSPPIRE Consortium. From August 22, 2012, to February 8, 2015, 155 children with ARP and 146 with CP (aged ≤19 years) were enrolled. Their demographic and clinical information was entered into the REDCap (Research Electronic Data Capture) database at the 15 centers. Differences were analyzed using 2-sample t test or Wilcoxon rank sum test for continuous variables and Pearson χ2 test or Fisher exact test for categorical variables. Disease burden variables (pain variables, hospital/emergency department visits, missed school days) were compared using Wilcoxon rank sum test.

Main Outcomes and Measures  Demographic characteristics, risk factors, abdominal pain, and disease burden.

Results  A total of 301 children were enrolled (mean [SD] age, 11.9 [4.5] years; 172 [57%] female); 155 had ARP and 146 had CP. The majority of children with CP (123 of 146 [84%]) reported prior recurrent episodes of acute pancreatitis. Sex distribution was similar between the groups (57% female in both). Hispanic children were less likely to have CP than ARP (17% vs 28%, respectively; odds ratio [OR] = 0.51; 95% CI, 0.29-0.92; P = .02). At least 1 gene mutation in pancreatitis-related genes was found in 48% of patients with ARP vs 73% of patients with CP (P < .001). Children with PRSS1 or SPINK1 mutations were more likely to present with CP compared with ARP (PRSS1: OR = 4.20; 95% CI, 2.14-8.22; P < .001; and SPINK1: OR = 2.30; 95% CI, 1.03-5.13; P = .04). Obstructive risk factors did not differ between children with ARP or CP (33% in both the ARP and CP groups), but toxic/metabolic risk factors were more common in children with ARP (21% overall; 26% in the ARP group and 15% in the CP group; OR = 0.55; 95% CI, 0.31-0.99; P = .046). Pancreatitis-related abdominal pain was a major symptom in 81% of children with ARP or CP within the last year. The disease burden was greater in the CP group compared with the ARP group (more emergency department visits, hospitalizations, and medical, endoscopic, and surgical interventions).

Conclusions and Relevance  Genetic mutations are common in both ARP and CP. Ethnicity and mutations in PRSS1 or SPINK1 may influence the development of CP. The high disease burden in pediatric CP underscores the importance of identifying predisposing factors for progression of ARP to CP in children.

Introduction

Acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) are poorly understood conditions of childhood.1 Single-center studies estimate that 9% to 35% of children with acute pancreatitis (AP) have recurrent episodes,25 and the incidence of CP is approximately 0.5 per 100 000 persons per year in young adults.6,7

Factors that predispose children to recurrent episodes of AP and progression from ARP to CP are unknown. Although alcohol use and smoking have long been recognized as major risk factors for ARP and CP in adults,8 they are uncommon in the pediatric age group. Recent single-center studies have identified several genetic risk factors in children with ARP or CP,4,5,914 including mutations in the following genes: cystic fibrosis transmembrane conductance regulator (CFTR), cationic trypsinogen (PRSS1), pancreatic secretory trypsin inhibitor (SPINK1), chymotrypsin C (CTRC), and carboxypeptidase 1 (CPA1). Other risk factors include obstructive, traumatic, infectious, and metabolic causes.15,16

Most of our current knowledge on ARP and CP comes from studies in adults. Because the etiologies of these diseases differ greatly between children and adults, applying the knowledge on the natural history and management of these diseases from adults to children may be inappropriate. The international, multicenter INSPPIRE (International Study Group of Pediatric Pancreatitis: In Search for a Cure) Consortium was created to address this issue by collecting data on the largest group of pediatric patients with ARP or CP to date.10,17 We have recently reported that genetic and obstructive factors are common in children with CP and that the associated disease burden is substantial.10

In this study, we analyzed the demographic and clinical characteristics of children with ARP and CP with the goal of identifying the risk factors and disease burden.

Box Section Ref ID

Key Points

  • Question What are the risk factors and disease burden of acute recurrent pancreatitis and chronic pancreatitis in children?

  • Findings In this cross-sectional study of children with acute recurrent pancreatitis and chronic pancreatitis, pancreatitis-associated gene mutations were the most common risk factor. Children with chronic pancreatitis were mostly of non-Hispanic ethnicity, had PRSS1 or SPINK1 mutations, and had higher disease burden than those with acute recurrent pancreatitis.

  • Meaning The high disease burden in pediatric chronic pancreatitis underscores the importance of identifying predisposing factors for development of chronic pancreatitis in children.

Methods
Study Design and Participants

In this cross-sectional study from 15 institutions, demographic and clinical data were collected in patient/parent and physician questionnaires on children who fulfilled the criteria for ARP or CP and were aged 19 years or younger at the time of enrollment.10,17 Acute recurrent pancreatitis was defined as 2 episodes of AP along with resolution of pain (≥1 month between episodes) or as normalization of pancreatic enzyme levels and resolution of pain between episodes irrespective of time interval.1 Diagnosis of CP required at least 1 of the following: (1) abdominal pain plus imaging findings suggestive of chronic pancreatic damage; (2) exocrine pancreatic insufficiency and imaging findings suggestive of chronic pancreatic damage; or (3) endocrine pancreatic insufficiency and imaging findings suggestive of chronic pancreatic damage.1 Information was entered into the REDCap (Research Electronic Data Capture) database from August 22, 2012, to February 8, 2015, and represented baseline information of the INSPPIRE cohort. All centers obtained institutional review board approval or the equivalent for their country. Written informed consent and/or assent was obtained from all parents and children. Seventy-six of the patients with CP were described in a previous study.10 We included patients with cystic fibrosis if they were pancreatic sufficient and having recurrent episodes of AP.

Statistical Analysis

Summary statistics were presented as mean with standard deviation, median with interquartile range (IQR), or frequency count with percentage. Patient characteristics, risk factors, and clinical variables were compared between ARP and CP using 2-sample t test or Wilcoxon rank sum test for continuous variables and using Pearson χ2 test or Fisher exact test for categorical variables. The results from these statistical tests were reported as difference of means or medians and as odds ratio (OR), respectively, with corresponding 95% confidence interval and P value. P < .05 was considered statistically significant. Statistical analysis was performed using SAS version 9.4 statistical software (SAS Institute, Inc).

Results
Patient Characteristics

Of the 301 patients in the INSPPIRE database (mean [SD] age, 11.9 [4.5] years; 172 [57%] female), 155 patients met the criteria for ARP and 146 for CP. Demographic characteristics of these patients are shown in Table 1, and their distribution across INSPPIRE centers is given in eTable 1 in the Supplement. Sex distribution was similar between the groups (57% female in both), and the majority of participants were white (81% in the ARP group and 80% in the CP group). Hispanic children were less likely to have CP than ARP (17% vs 28%, respectively; OR = 0.51; 95% CI, 0.29-0.92). Children with CP tended to be older at the time of first diagnosis of pancreatitis compared with those who had ARP, but the difference was not statistically significant (mean [SD] age, 10.2 [4.5] vs 9.1 [5.0] years, respectively; mean difference, 1.1 years; 95% CI, −0.1 to 2.3; P = .08). Of the 146 children with CP, 123 (84%) had documented prior episodes of ARP. The date of first AP episode and the date of CP diagnosis used to calculate time for progressing from ARP to CP were available in 76 of these 123 patients; the median time was 1 year (IQR, 1.5 months to 2.7 years; range, 0-14.3 years).

Family history of AP was similar between the groups, but patients with CP were more likely than those with ARP to have a family history of CP (36% vs 16%, respectively; OR = 3.12; 95% CI, 1.70-5.73; P < .001). Chronic pancreatitis was less common in Hispanic patients than in non-Hispanic patients (OR = 0.51; 95% CI, 0.29-0.92; P = .02) (eTable 2 in the Supplement).

Risk Factors

Risk factors were divided into 4 categories: genetic (CFTR, SPINK1, PRSS1, CTRC), obstructive, toxic/metabolic, and autoimmune. At least 1 risk factor was identified in 111 patients with ARP (72%) and 125 patients with CP (86%). The most common risk factors for development of ARP or CP were genetic and obstructive (Table 2).

At least 1 gene mutation in pancreatitis-related genes was found in 49 of 102 patients with ARP (48%) and 86 of 118 patients with CP (73%) (P < .001). Of the 53 patients with ARP in whom no mutations were identified, 18 were screened for 2 or fewer gene mutations. Of the 32 patients with CP who had no identified mutations, 6 were tested for fewer than 3 gene mutations.

The most common mutation identified in ARP was in CFTR (30 of 89 patients [34%]), and the most common mutation identified in CP was in PRSS1 (50 of 108 patients [46%]). Six children in the ARP group and 2 in the CP group had cystic fibrosis as determined by 2 CFTR disease-causing mutations and/or abnormal sweat chloride level. Children with PRSS1 or SPINK1 mutations were more likely to present with CP compared with ARP (PRSS1: OR = 4.20; 95% CI, 2.14-8.22; P < .001; and SPINK1: OR = 2.30; 95% CI, 1.03-5.13; P = .04).

Some children had more than 1 genetic risk factor. In children who had 3 or more genes tested, 8 of 84 patients with ARP (10%) and 17 of 112 patients with CP (15%) had more than 1 genetic risk factor. A combination of CFTR and SPINK1 mutations was most common (found in 5 children with ARP and 9 with CP).

Obstructive risk factors were found in 33% of patients and toxic/metabolic factors were found in 21% (Table 2). Pancreas divisum (PD) was present in 13 of 146 children with ARP (9%) and 22 of 140 children with CP (16%). It was less frequent with PRSS1 mutations (eTable 3 in the Supplement). Obstructive and autoimmune risk factors were not significantly different between children with ARP and those with CP. Children with CP as compared with those with ARP less commonly had toxic/metabolic factors (22 of 137 children with CP [16%] vs 39 of 152 children with ARP [26%]; OR = 0.55; 95% CI, 0.31-0.99; P = .046) and specifically medications (ie, azathioprine sodium and 6-mercaptopurine; 4 of 87 children with CP [5%] vs 19 of 108 children with ARP [18%]; OR = 0.23; 95% CI, 0.07-0.69; P = .005). Alcohol use (1%) and cigarette smoking (4%) were uncommon in pediatric ARP or CP. Sixteen of 112 children with ARP (14%) and 14 of 108 children with CP (13%) were diagnosed as having autoimmune pancreatitis (AIP). Only 1 child with CP had an elevated IgG4 level, consistent with type 1 AIP.

Children with ARP or CP often had multiple risk factors. At least 1 risk factor was identified in 111 of 155 patients with ARP (72%), and 47 of 155 (30%) had multiple risk factors from different categories present. In the remaining 44 patients with ARP, only 8 were evaluated for all 4 genes and other risk factors. Of the 146 patients with CP, at least 1 risk factor was identified in 125 (86%), and 40 (27%) had multiple risk factors present. In the remaining 21 patients with CP, only 4 tested negative for all 4 genetic risk factors as well as other risk factors.

Burden of Disease

Pancreatitis-related abdominal pain was a major symptom in 81% of children with ARP or CP within the last year. The pain was mostly episodic in both groups (Table 3). Although constant and episodic pain scores were slightly higher in CP, the differences were not significant. The numbers of emergency department (ED) visits and hospitalizations were higher in patients with CP compared with ARP (lifelong ED visits: median [IQR], 4.5 [1-10] vs 2 [1-4], respectively; median difference, 2.5 visits; 95% CI, 1.4-3.6; P < .001; lifelong hospitalizations: median [IQR], 4 [1-8] vs 2 [1-4], respectively; median difference, 2.0; 95% CI, 1.0-3.0; P < .001), but no differences were found between groups for ED visits and hospitalizations within the past year (Table 3). Children with CP missed a median of 2 days (IQR, 0-6 days) of school in the past month, whereas the median was 0 days (IQR, 0-5 days) for children with ARP; however, the difference was not statistically significant (median difference, 2 days; 95% CI, 0.2-3.8).

Table 4 summarizes all imaging studies performed on children with ARP or CP. Overall, imaging studies were more frequently ordered for CP compared with ARP. Magnetic retrograde cholangiopancreatography was the most commonly used imaging modality; some children with CP had endoscopic retrograde cholangiopancreatography performed up to 9 times since their diagnosis. As expected, children with ARP had findings consistent with AP (pancreas enlargement, focal AP, inflammatory changes) compared with children with CP, who had evidence of persistent pancreatic injury (atrophy; calcifications; ductal irregularities, obstruction, dilatation, or stones; abnormal side branches).

Children with CP were more likely to receive medical, endoscopic, and surgical therapies compared with those who had ARP (Table 5). Medical therapy primarily consisted of pain medications and pancreatic enzymes. Acetaminophen and ibuprofen were the leading pain medications for ARP, while patients with CP used acetaminophen and hydrocodone bitartrate for pain. Therapeutic endoscopic retrograde cholangiopancreatography was performed in only 14% of children with ARP compared with 68% of those with CP. The most common type of surgery for pediatric ARP was cholecystectomy: 8 were performed for pain, 3 for recurrent episodes of AP, and 1 for both pain and recurrent episodes of AP. Pain did not resolve after cholecystectomy (0 of 9 patients); recurrent pancreatitis resolved in 2 of 4 patients. Lateral pancreaticojejunostomy, partial pancreatectomy, total pancreatectomy or islet cell autotransplantation, and celiac plexus block were exclusively performed in CP.

Discussion

This international, multicenter study is the largest characterized cohort of children with ARP and CP and, to our knowledge, it is the first observational study comparing a large number of children with ARP vs children with CP. Most children with CP described a history of ARP and tended to be older at the time of diagnosis compared with children with ARP, suggesting that ARP and CP are a disease continuum. A large proportion of children with ARP or CP had multiple risk factors, suggesting the multifactorial nature of these conditions. The clustering of PRSS1 or SPINK1 mutations in children with CP raises the possibility that these gene mutations are important risk factors for progression from ARP to CP in the pediatric population. The disease burden was higher in CP compared with ARP, suggesting the importance of identifying early interventions to prevent or delay progression from ARP to CP.

Among the risk factors analyzed, an underlying genetic predisposition was most commonly found in our patients, almost 50% in ARP and approaching 75% in CP. Our findings agree with previous reports showing genetic mutations as common risk factors in children with ARP or CP.9,12,14,18,19 We may be underestimating the impact of gene mutations as risk factors for ARP or CP because we do not have analysis of the most commonly tested genes (PRSS1, CFTR, SPINK1, CTRC) for every patient in the database, as gene testing for INSPPIRE patients was at the physician’s discretion. Some of the newly discovered pancreatitis susceptibility genes also were not tested, as tests for them were not commercially available (CPA1, CLDN2, CEL, CEL-HYB).11,2022

To our knowledge, the natural history of pediatric pancreatitis has not been systematically investigated in children. Most of the data in adults that support progression of ARP to CP come from hereditary pancreatitis populations.23,24 Indeed, pancreatitis follows a severe course in patients with PRSS1 mutations (particularly R122H and N29I) with first episodes by approximately 10 years of age and progression to CP within the subsequent decade. Our findings support the hypothesis that PRSS1 is involved in progression from ARP to CP in children as well.

The role of SPINK1 mutations as a cause of pancreatitis is debated because these mutations can be found in 1% to 3% of the general population. We report a higher percentage of SPINK1 mutations in the INSPPIRE cohort (13% of those with ARP; 25% of those with CP). Similarly, SPINK1 N34S mutations have been found in approximately 25% of children with ARP or CP, a higher percentage compared with the general population.12,19,25 In addition, people with SPINK1 mutations are more prone to ARP or CP if mutations in other pancreatitis-relevant genes are also present (ie, PRSS1, CFTR, CTRC), with up to 900-fold increased risk by having both CFTR and SPINK1 mutations.2628 In our cohort, CFTR and SPINK1 mutations were commonly associated. Taken together, SPINK1 mutations (alone or in combination with other risk factors) may be playing a role in pediatric ARP and CP development.

We found PD in 9% to 16% of children with ARP and CP, similar to the frequency found in autopsy studies (5%-10%).29 It was associated with decreased frequency in children with PRSS1 mutations. Most studies reporting association of PD with ARP or CP, similar to this study, are based on symptomatic patients who had imaging studies done for the evaluation of pancreatitis. The involvement of PD in the pathogenesis of ARP or CP needs to be further studied.

We found that a large subset of children with ARP or CP had more than 1 identifiable risk factor, including patients with more than 1 risk factor in a single category (genetic factors) and patients with a combination of factors across categories. Our observations are consistent with previous studies suggesting that the pathogenesis of ARP or CP is multifactorial.

We observed that most of the children with ARP and CP were white and CP was less common in patients with Hispanic ethnicity. This is likely due to genetic mutations found in white individuals and not referral bias in our study. In a recent analysis of 2 large national databases that included more than 1.5 million hospitalized US children, CP was also found more commonly in white patients.30 The possible reduced risk noted in our pediatric Hispanic population may be explained by the lower prevalence of PRSS1 and SPINK1 mutations in this group.

Most of the children in our study reported pancreatitis-related pain within the previous year; the pain was chronic in one-third of the patients. The disease burden was higher in the CP group compared with the ARP group (significantly more ED visits and hospitalizations; significantly more medical, endoscopic, and surgical therapies; and more missed school days). Pancreatitis causes a serious burden on the health care system, with AP being the top gastrointestinal cause for admission in adults.31 With increasing incidence of AP in childhood,32,33 we expect that the disease burden in our cohort is substantial.

We were surprised by the large number of children with AIP in our cohort. The diagnosis of AIP in the medical literature is limited to few case reports.34 As previously reported, most children with AIP in our study had type 2. Our future goal is to develop diagnostic and therapeutic criteria for pediatric AIP. These guidelines will be aimed to better phenotype children in our database as well as to bring a unifying definition to this disease.

Our study has several limitations. The prevalence of genetic predisposing factors was underestimated because not every patient underwent genetic testing and when they did, it was not always complete. Newly identified pancreatitis-associated genes could not be identified in our population, as tests are not commercially available. Moving forward, we plan to test INSPPIRE patients for all pancreatitis-relevant genes. While we acknowledge a potential referral bias from large referral centers in our study, we note that a center that performed most islet cell transplants (University of Minnesota) contributed approximately 10% to our cohort (eTable 1 in the Supplement). The analysis of children with ARP or CP was done at the time of enrollment; therefore, assessment of risk factors could not be done over time as children progressed from ARP to CP. Nevertheless, the large number of well-phenotyped patients with ARP or CP allowed us to compare the characteristics of these children. Our study is underpowered to study the role of cholecystectomy on relieving recurrent disease. Prospective data collection is more likely to shed light on this question. Through a prospective registry of longitudinal clinical data, INSPPIRE aims to determine the natural course of pediatric ARP and CP and identify risk factors for the progression to CP.

Conclusions

Pancreatitis-associated gene mutations are the most common risk factors in children with ARP or CP, and multiple risk factors are usually coexistent. The socioeconomic burden of disease is significant given the presence of pain, health care visits, and number of diagnostic tests performed. Further work will focus on analyzing the impact of genetic and other risk factors on the natural history of pediatric pancreatitis and its sequelae and developing a standardized approach to the evaluation of children with ARP or CP.

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Corresponding Author: Aliye Uc, MD, Stead Family Department of Pediatrics, University of Iowa Children’s Hospital, University of Iowa Carver College of Medicine, BT 1120-C, 200 Hawkins Dr, Iowa City, IA 52242 (aliye-uc@uiowa.edu).

Accepted for Publication: December 24, 2015.

Published Online: April 11, 2016. doi:10.1001/jamapediatrics.2015.4955.

Author Contributions: Drs Kumar, Ooi, and Werlin contributed equally to the manuscript. Drs Zimmerman and Uc had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Ooi, Werlin, Abu-El-Haija, Bellin, Durie, Fishman, Freedman, Giefer, Gonska, Heyman, Husain, Lin, Lowe, Morinville, Pohl, Schwarzenberg, Wilschanski, Uc.

Acquisition, analysis, or interpretation of data: Kumar, Ooi, Werlin, Barth, Bellin, Fishman, Freedman, Gariepy, Giefer, Heyman, Himes, Lin, Lowe, Morinville, Palermo, Schwarzenberg, Troendle, Wilschanski, Zimmerman, Uc.

Drafting of the manuscript: Kumar, Ooi, Werlin, Freedman, Lin, Wilschanski, Uc.

Critical revision of the manuscript for important intellectual content: Ooi, Abu-El-Haija, Barth, Bellin, Durie, Fishman, Freedman, Gariepy, Giefer, Gonska, Heyman, Himes, Husain, Lin, Lowe, Morinville, Palermo, Pohl, Schwarzenberg, Troendle, Wilschanski, Zimmerman, Uc.

Statistical analysis: Ooi, Zimmerman, Uc.

Obtained funding: Gariepy, Morinville, Uc.

Administrative, technical, or material support: Abu-El-Haija, Barth, Giefer, Gonska, Heyman, Himes, Morinville, Pohl, Troendle, Uc.

Study supervision: Durie, Freedman, Heyman, Husain, Lowe, Schwarzenberg, Uc.

Conflict of Interest Disclosures: Dr Fishman reported serving as a consultant to Pentax Medical Imaging, Cook Medical, and Norgine Pharmaceuticals and serving as a contributor to UpToDate. Dr Gonska reported receiving research funding from Vertex Pharmaceuticals, Al Qamra Inc, Glaxo Smith Kline Inc, Pfizer, and Cystic Fibrosis Foundation Therapeutics. Dr Heyman reported serving as editor of the Journal of Pediatric Gastroenterology and Nutrition. Dr Lin reported serving as associate editor of the Journal of Pediatric Gastroenterology and Nutrition. Dr Lowe reported serving as a consultant to Nordmark Arzneimittel GmbH & Co KG. Dr Pohl reported serving on the editorial board of Practical Gastroenterology and serving as a speaker’s bureau member for Medical Education Resources, Inc. Dr Schwarzenberg reported serving as a consultant to the Cystic Fibrosis Foundation. No other disclosures were reported.

Funding/Support: This work was supported by grants DK096327 (Dr Uc) and DK108334 (Dr Uc) and Clinical and Translational Science Award UL1 TR000442 from the National Institutes of Health.

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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