Impact of Elevated Serum Triglycerides on Children with Acute Recurrent or Chronic Pancreatitis from INSPPIRE-2.

OBJECTIVE: To determine if mild-moderate hypertriglyceridemia (HTG) is associated with increased development of chronic pancreatitis (CP) or pancreatitis-associated complications in children with acute recurrent or CP. STUDY DESIGN: Longitudinal data from the INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2) cohort of children with acute recurrent or CP (n = 559) were analyzed. Subjects were divided into normal triglycerides (<150 mg/dL; 1.7 mmol/L), any HTG (≥150 mg/dL; ≥1.7 mmol/L), mild-moderate HTG (150-499 mg/dL; 1.7-5.6 mmol/L), moderate HTG (500-999 mg/dL; 5.6-11.3 mmol/L), and severe HTG groups (≥1000 mg/dL; ≥11.3 mmol/L), based on highest serum triglyceride value. Laboratory, imaging, pancreatitis and hospital events, complications, and quality of life data were analyzed. RESULTS: In children with acute recurrent or CP and HTG, there was no increase in the number of pancreatitis attacks per person-years, nor an increase in CP prevalence. However, HTG severity was associated with increased pancreatic inflammation, pancreatic cysts, pain, hospital days, number of hospitalizations, intensive care, and missed school days. CONCLUSIONS: Mild-moderate HTG in children with acute recurrent or CP was not associated with increased pancreatitis frequency, nor increased development of CP, but was associated with increased pancreatitis complications and disease burden. As a treatable condition, treatment of mild-moderate HTG may be considered to reduce pancreatitis-associated complications and medical burden in children with acute recurrent or CP.

Pancreatic Enzyme Use Reduces Pancreatitis Frequency in Children With Acute Recurrent or Chronic Pancreatitis: A Report From INSPPIRE.

INTRODUCTION: Among children who suffer from acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP), acute pancreatitis (AP) episodes are painful, often require hospitalization, and contribute to disease complications and progression. Despite this recognition, there are currently no interventions to prevent AP episodes. In this retrospective cohort study, we assessed the impact of pancreatic enzyme therapy (PERT) use on clinical outcomes among children with pancreatic-sufficient ARP or CP. METHODS: Children with pancreatic-sufficient ARP or CP in the INSPPIRE-2 cohort were included. Clinical outcomes were compared for those receiving vs not receiving PERT, as well as frequency of AP before and after PERT. Logistic regression was used to study the association between development of AP episodes after starting PERT and response predictors. RESULTS: Among 356 pancreatic-sufficient participants, 270 (76%) had ARP, and 60 (17%) received PERT. Among those on PERT, 42% did not have a subsequent AP episode, during a mean 2.1 years of follow-up. Children with a SPINK1 mutation ( P = 0.005) and those with ARP (compared with CP, P = 0.008) were less likely to have an AP episode after starting PERT. After initiation of PERT, the mean AP annual incidence rate decreased from 3.14 down to 0.71 ( P < 0.001). DISCUSSION: In a retrospective analysis, use of PERT was associated with a reduction in the incidence rate of AP among children with pancreatic-sufficient ARP or CP. These results support the need for a clinical trial to evaluate the efficacy of PERT to improve clinical outcomes among children with ARP or CP.

Demographics and risk factors for pediatric recurrent acute pancreatitis.

PURPOSE OF REVIEW: Approximately 20-30% of children who experience one episode of acute pancreatitis will have at least one additional episode. For some children, pancreatitis recurs multiple times and in a few years is followed by the diagnosis of chronic pancreatitis. Identifying risk factors for recurrent episodes and disease progression is critical to developing therapeutic interventions. RECENT FINDINGS: Obesity is driving an increase in biliary stone disease and severe acute pancreatitis. Recurrent acute pancreatitis (RAP) may lead to the development of diabetes through autoimmune mechanisms. Cystic fibrosis or CFTR-related disorders may present as RAP and CFTR modulator therapy can increase or decrease the risk of acute pancreatitis in these populations. Children with Crohn disease have a three-fold risk of acute pancreatitis over the general population while children with ulcerative colitis are at increased risk for pediatric autoimmune pancreatitis, a disorder that may be distinct from autoimmune pancreatitis described in adults. Obstructive jaundice in the absence of identified mechanical factors may be a presenting sign of pediatric autoimmune pancreatitis. SUMMARY: Pediatric RAP is a painful condition that leads to gland destruction and functional insufficiency. Risk factors are being clarified but preventive treatments remain elusive.

National Trends of Hospitalizations in Cystic Fibrosis Highlight a Need for Pediatric to Adult Transition Clinics.

OBJECTIVES: We hypothesized that hospitalizations in cystic fibrosis (CF) would reflect the development of age-related comorbidities. METHODS: A retrospective analysis was performed using the Nationwide Inpatient Sample (2002-2017). Hospitalizations for which the principal diagnosis was CF were analyzed regarding age at discharge and presence of comorbidities. Trends were assessed for significance using the Cochran-Armitage test. RESULTS: The mean age of patients hospitalized for CF increased from 19.7 years in 2002 to 23.0 years in 2017 (P = 0.017). Several comorbidities are more than 10 times more prevalent among adults as compared with children, including congestive heart failure, substance abuse, and chronic kidney disease (P < 0.001). In addition, diabetes with chronic complications was more prevalent in adults than children (10.0% vs 3.9%; P < 0.001), as was hypertension (7.2% vs 1.3%; P < 0.001) and osteoporosis (10.2% vs 1.9%; P < 0.001). More than 65% of CF hospitalizations in 2017 were in individuals older than 18 years. CONCLUSIONS: Hospitalizations for adults with CF are increasing, and individuals with CF are developing age-related comorbidities. Providers equipped to manage the health care needs of adults need to be ready and able to care for this unique and growing patient population.

Web-based cognitive-behavioral intervention for pain in pediatric acute recurrent and chronic pancreatitis: Protocol of a multicenter randomized controlled trial from the study of chronic pancreatitis, diabetes and pancreatic cancer (CPDPC).

INTRODUCTION: Abdominal pain is common and is associated with high disease burden and health care costs in pediatric acute recurrent and chronic pancreatitis (ARP/CP). Despite the strong central component of pain in ARP/CP and the efficacy of psychological therapies for other centralized pain syndromes, no studies have evaluated psychological pain interventions in children with ARP/CP. The current trial seeks to 1) evaluate the efficacy of a psychological pain intervention for pediatric ARP/CP, and 2) examine baseline patient-specific genetic, clinical, and psychosocial characteristics that may predict or moderate treatment response. METHODS: This single-blinded randomized placebo-controlled multicenter trial aims to enroll 260 youth (ages 10-18) with ARP/CP and their parents from twenty-one INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In search for a cuRE) centers. Participants will be randomly assigned to either a web-based cognitive behavioral pain management intervention (Web-based Management of Adolescent Pain Chronic Pancreatitis; WebMAP; N = 130) or to a web-based pain education program (WebED; N = 130). Assessments will be completed at baseline (T1), immediately after completion of the intervention (T2) and at 6 months post-intervention (T3). The primary study outcome is abdominal pain severity. Secondary outcomes include pain-related disability, pain interference, health-related quality of life, emotional distress, impact of pain, opioid use, and healthcare utilization. CONCLUSIONS: This is the first clinical trial to evaluate the efficacy of a psychological pain intervention for children with CP for reduction of abdominal pain and improvement of health-related quality of life. Findings will inform delivery of web-based pain management and potentially identify patient-specific biological and psychosocial factors associated with favorable response to therapy. Clinical Trial Registration #: NCT03707431.

Chronic Pancreatitis: Pediatric and Adult Cohorts Show Similarities in Disease Progress Despite Different Risk Factors.

OBJECTIVES: The aim of the present study was to investigate the natural history of chronic pancreatitis (CP); patients in the North American Pancreatitis Study2 (NAPS2, adults) and INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE, pediatric) were compared. METHODS: Demographics, risk factors, disease duration, management and outcomes of 224 children and 1063 adults were compared using appropriate statistical tests for categorical and continuous variables. RESULTS: Alcohol was a risk in 53% of adults and 1% of children (P < 0.0001); tobacco in 50% of adults and 7% of children (P < 0.0001). Obstructive factors were more common in children (29% vs 19% in adults, P = 0.001). Genetic risk factors were found more often in children. Exocrine pancreatic insufficiency was similar (children 26% vs adult 33%, P = 0.107). Diabetes was more common in adults than children (36% vs 4% respectively, P < 0.0001). Median emergency room visits, hospitalizations, and missed days of work/school were similar across the cohorts. As a secondary analysis, NAPS2 subjects with childhood onset (NAPS2-CO) were compared with INSPPIRE subjects. These 2 cohorts were more similar than the total INSPPIRE and NAPS2 cohorts, including for genetic risk factors. The only risk factor significantly more common in the NAPS2-CO cohort compared with the INSPPIRE cohort was alcohol (9% NAPS2-CO vs 1% INSPPIRE cohorts, P = 0.011). CONCLUSIONS: Despite disparity in age of onset, children and adults with CP exhibit similarity in demographics, CP treatment, and pain. Differences between groups in radiographic findings and diabetes prevalence may be related to differences in risk factors associated with disease and length of time of CP.

INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE Cohort Study: Design and Rationale for INSPPIRE 2 From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer.

We created the INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE (INSPPIRE 2) cohort to study the risk factors, natural history, and outcomes of pediatric acute recurrent pancreatitis and chronic pancreatitis (CP). Patient and physician questionnaires collect information on demographics, clinical history, family and social history, and disease outcomes. Health-related quality of life, depression, and anxiety are measured using validated questionnaires. Information entered on paper questionnaires is transferred into a database managed by Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer's Coordinating and Data Management Center. Biosamples are collected for DNA isolation and analysis of most common pancreatitis-associated genes.Twenty-two sites (18 in the United States, 2 in Canada, and 1 each in Israel and Australia) are participating in the INSPPIRE 2 study. These sites have enrolled 211 subjects into the INSPPIRE 2 database toward our goal to recruit more than 800 patients in 2 years. The INSPPIRE 2 cohort study is an extension of the INSPPIRE cohort study with a larger and more diverse patient population. Our goals have expanded to include evaluating risk factors for CP, its sequelae, and psychosocial factors associated with pediatric acute recurrent pancreatitis and CP.

Early-Onset Acute Recurrent and Chronic Pancreatitis Is Associated with PRSS1 or CTRC Gene Mutations.

OBJECTIVES: To assess whether the age of onset was associated with unique features or disease course in pediatric acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). STUDY DESIGN: Demographic and clinical information on children with ARP or CP was collected at INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE) centers. The Cochran-Armitage trend test and Jonckheere-Terpstra test were used to examine for differences between pediatric age groups (<6, 6-11, and ≥12 years). RESULTS: Between September 2012 and March 2016, 342 children with ARP or CP were enrolled; 129 (38%) were <6 years of age at the time of first diagnosis of acute pancreatitis, 111 (32%) were 6-11 years of age, and 102 (30%) were ≥12 years of age. Early-onset disease was associated with mutations in cationic trypsinogen (PRSS1) (P < .01), chymotrypsin C (CTRC) (P = .01), family history of acute pancreatitis (P = .02), family history of CP (P < .01), biliary cysts (P = .04), or chronic renal failure (P = .02). Later-onset disease was more commonly present with hypertriglyceridemia (P = .04), ulcerative colitis (P = .02), autoimmune diseases (P < .0001), or medication use (P < .01). Children with later-onset disease also were more likely to visit the emergency department (P < .05) or have diabetes (P < .01). CONCLUSIONS: Early-onset pancreatitis is associated strongly with PRSS1 or CTRC mutations and family history of pancreatitis. Children with later-onset disease are more likely to have nongenetic risk factors. Future studies are needed to investigate whether the disease course, response to therapy, or clinical outcomes differ relative to the timing of disease onset.

Direct Costs of Acute Recurrent and Chronic Pancreatitis in Children in the INSPPIRE Registry.

OBJECTIVE: To estimate selected direct medical care costs of children with chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP). METHODS: We performed a cross-sectional study of data from International Study Group of Pediatric Pancreatitis: In Search for a Cure (INSPPIRE), a multinational registry of children with ARP or CP. We determined health care utilization and estimated costs of hospitalizations, surgical and endoscopic procedures, and medications in our study population. Health care utilization data were obtained from all subjects enrolled in the study, and costs were calculated using national United States costs. RESULTS: We included 224 subjects (median age 12.7 years), 42% of whom had CP. Mean number of hospitalizations, including for surgery and endoscopic retrograde cholangiopancreatography, was 2.3 per person per year, costing an estimated average $38,755 per person per year. Including outpatient medications, estimated total mean cost was $40,589 per person per year. Subjects using surgical procedures or endoscopic retrograde cholangiopancreatography incurred mean annual costs of $42,951 per person and $12,035 per person, respectively. Estimated annual costs of pancreatic enzyme replacement therapy, diabetic medications, and pain medications were $4114, $1761, and $614 per person, respectively. In an exploratory analysis, patients with the following characteristics appear to accrue higher costs than those without them: more frequent ARP attacks per year, reported constant or episodic pain, family history of pancreatic cancer, and use of pain medication. CONCLUSIONS: ARP and CP are uncommon childhood conditions. The severe burden of disease associated with these conditions and their chronicity results in high health care utilization and costs. Interventions that reduce the need for hospitalization could lower costs for these children and their families.

Pediatric chronic pancreatitis is associated with genetic risk factors and substantial disease burden.

OBJECTIVE: To determine the clinical presentation, diagnostic variables, risk factors, and disease burden in children with chronic pancreatitis. STUDY DESIGN: We performed a cross-sectional study of data from the International Study Group of Pediatric Pancreatitis: In Search for a Cure, a registry of children with acute recurrent pancreatitis and chronic pancreatitis. Between-group differences were compared using Wilcoxon rank-sum test. RESULTS: Among 170 subjects in the registry, 76 (45%) had chronic pancreatitis; 57% were female, 80% were white; median age at diagnosis was 9.9 years. Pancreatitis-predisposing genetic mutations were identified in 51 (67%) and obstructive risk factors in 25 (33%). Toxic/metabolic and autoimmune factors were uncommon. Imaging demonstrated ductal abnormalities and pancreatic atrophy more commonly than calcifications. Fifty-nine (77%) reported abdominal pain within the past year; pain was reported as constant and receiving narcotics in 28%. Children with chronic pancreatitis reported a median of 3 emergency department visits and 2 hospitalizations in the last year. Forty-seven subjects (70%) missed 1 day of school in the past month as the result of chronic pancreatitis; 26 (34%) missed 3 or more days. Children reporting constant pain were more likely to miss school (P = .002), visit the emergency department (P = .01), and experience hospitalizations (P = .03) compared with children with episodic pain. Thirty-three children (43%) underwent therapeutic endoscopic retrograde pancreatography; one or more pancreatic surgeries were performed in 30 (39%). CONCLUSIONS: Chronic pancreatitis occurs at a young age with distinct clinical features. Genetic and obstructive risk factors are common, and disease burden is substantial.

Clinical management of motility disorders in children.

We review the current clinical evaluation and management of the most common esophageal and gastrointestinal motility disorders in children based on the literature and our experience in a pediatric motility center in the United States. The disorders discussed include esophageal achalasia, pre- and post-fundoplication motility disorders, gastroparesis, motility disorders occurring after repair of congenital atresias, motility disorders associated with gastroschisis, chronic intestinal pseudo-obstruction, motility after intestinal transplantation, motility disorders after colonic resection for Hirschsprung's disease, chronic functional constipation, and motility disorders associated with imperforate anus.