Acute and Chronic Pancreatitis Disease Prevalence, Classification, and Comorbidities: A Cohort Study of the UK BioBank.

INTRODUCTION: Pancreatitis is a complex syndrome that results from many etiologies. Large well-characterized cohorts are needed to further understand disease risk and prognosis. METHODS: A pancreatitis cohort of more than 4,200 patients and 24,000 controls were identified in the UK BioBank (UKBB) consortium. A descriptive analysis was completed, comparing patients with acute (AP) and chronic pancreatitis (CP). The Toxic-metabolic, Idiopathic, Genetic, Autoimmune, Recurrent, and severe pancreatitis and Obstructive checklist Version 2 classification was applied to patients with AP and CP and compared with the control population. RESULTS: CP prevalence in the UKBB is 163 per 100,000. AP incidence increased from 21.4/100,000 per year from 2001 to 2005 to 48.2/100,000 per year between 2016 and 2020. Gallstones and smoking were confirmed as key risk factors for AP and CP, respectively. Both populations carry multiple risk factors and a high burden of comorbidities, including benign and malignant neoplastic disorders. DISCUSSION: The UKBB serves as a rich cohort to evaluate pancreatitis. Disease burden of AP and CP was high in this population. The association of common risk factors identified in other cohort studies was confirmed in this study. Further analysis is needed to link genomic risks and biomarkers with disease features in this population.

Introduction and Validation of a Novel Acute Pancreatitis Digital Tool: Interrogating Large Pooled Data From 2 Prospectively Ascertained Cohorts.

OBJECTIVES: Acute pancreatitis (AP) is a sudden onset, rapidly evolving inflammatory response with systemic inflammation and multiorgan failure (MOF) in a subset of patients. New highly accurate clinical decision support tools are needed to allow local doctors to provide expert care. METHODS: Ariel Dynamic Acute Pancreatitis Tracker (ADAPT) is a digital tool to guide physicians in ordering standard tests, evaluate test results and model progression using available data, propose emergent therapies. The accuracy of the severity score calculators was tested using 2 prospectively ascertained Acute Pancreatitis Patient Registry to Examine Novel Therapies in Clinical Experience cohorts (pilot University of Pittsburgh Medical Center, n = 163; international, n = 1544). RESULTS: The ADAPT and post hoc expert-calculated AP severity scores were 100% concordant in both pilot and international cohorts. High-risk criteria of all 4 severity scores at admission were associated with moderately-severe or severe AP and MOF (both P < 0.0001) and prediction of no MOF was 97.8% to 98.9%. The positive predictive value for MOF was 7.5% to 14.9%. CONCLUSIONS: The ADAPT tool showed 100% accuracy with AP predictive metrics. Prospective evaluation of ADAPT features is needed to determine if additional data can accurately predict and mitigate severe AP and MOF.

Complex Genetics in Pancreatitis: Insights Gained From a New Candidate Locus Panel.

OBJECTIVES: Chronic pancreatitis is the end stage of a pathologic inflammatory syndrome with multiple etiological factors, including genetic. We hypothesized that some pancreatitis etiology originates in pancreatic acinar or duct cells and requires both injury and compensatory mechanism failure. METHODS: One hundred pancreatitis patients were assessed using a DNA sequencing panel for pancreatitis. Cooccurrence of variants within and between genes was measured. Gene coexpression was confirmed via published single-cell RNA sequencing. RESULTS: One hundred and twenty-one variants were identified in 2 or more patients, 15 of which were enriched compared with reference populations. Single cell RNA-sequencing data verified coexpression of GGT1, CFTR, and PRSS1 in duct cells, PRSS1, CPA1, CEL, CTRC, and SPINK1 in acinar cells, and UBR1 in both. Multiple-risk variants with injury/stress effects (CEL, CFTR, CPA1, PRSS1) and impaired cell protection (CTRC, GGT1, SPINK1, UBR1) cooccur within duct cells, acinar cells, or both. CONCLUSIONS: Pancreatitis is a complex disorder with genetic interactions across genes and cell types. These findings suggest a new, non-Mendelian genetic risk/etiology paradigm where a combination of nonpathogenic genetic risk variants in groups of susceptibility genes and injury/dysfunction response genes contribute to acquired pancreatic disease.

Hospitalization rates among patients with cystic fibrosis using pancreatic enzyme replacement therapy.

We investigated the relationship between self-reported adherence to pancreatic enzyme replacement therapy (PERT), nutritional status, and all-cause hospitalization in cystic fibrosis (CF) patients with a record of PERT use. Association of self-reported annual PERT use rate (adherence) with annual hospital admission rate (HAR) and annual total hospital nights (THNs) were analyzed for 5301 children (2000-2012) and 13,989 adults (2000-2013) from the CF Foundation Patient Registry. Multivariate linear regression was used to determine the association of HAR and THN with mean annual PERT use rate, cumulative PERT use rate, mean body mass index (BMI) (adult) or BMI percentile (pediatric), age, and sex. The median annual PERT use rate was 87% in children and 80% in adults. Statistically, higher annual PERT use, longer cumulative PERT, and higher BMI percentile (children) or BMI (adults) were significantly (p < 0.0001) associated with lower annual HAR and fewer annual THN in children and adults. Female sex was associated with higher annual HAR and more annual THN in children and adults (p < 0.05). Results indicate self-reported adherence to PERT, increased BMI, and male sex were associated with fewer hospital admissions and annual hospital nights in CF patients.

Precision Medicine in Pancreatic Disease-Knowledge Gaps and Research Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop.

A workshop on research gaps and opportunities for Precision Medicine in Pancreatic Disease was sponsored by the National Institute of Diabetes and Digestive Kidney Diseases on July 24, 2019, in Pittsburgh. The workshop included an overview lecture on precision medicine in cancer and 4 sessions: (1) general considerations for the application of bioinformatics and artificial intelligence; (2) omics, the combination of risk factors and biomarkers; (3) precision imaging; and (4) gaps, barriers, and needs to move from precision to personalized medicine for pancreatic disease. Current precision medicine approaches and tools were reviewed, and participants identified knowledge gaps and research needs that hinder bringing precision medicine to pancreatic diseases. Most critical were (a) multicenter efforts to collect large-scale patient data sets from multiple data streams in the context of environmental and social factors; (b) new information systems that can collect, annotate, and quantify data to inform disease mechanisms; (c) novel prospective clinical trial designs to test and improve therapies; and (d) a framework for measuring and assessing the value of proposed approaches to the health care system. With these advances, precision medicine can identify patients early in the course of their pancreatic disease and prevent progression to chronic or fatal illness.

Accelerating the Drug Delivery Pipeline for Acute and Chronic Pancreatitis: Summary of the Working Group on Drug Development and Trials in Recurrent Acute Pancreatitis at the National Institute of Diabetes and Digestive and Kidney Diseases Workshop.

Recurrent acute pancreatitis (RAP) is a complex clinical syndrome with significant morbidity, unpredictable outcomes, and limited treatment options. The National Institute of Diabetes and Digestive and Kidney Disease sponsored a workshop on July 25, 2018, in Pittsburgh, Pennsylvania, to address research gaps impeding development of effective therapies for pancreatitis. The RAP working group identified challenges to clinical progress using existing definitions, risk assessment, diagnostic and severity criteria, disease trajectories, outcomes, and research methods. Recurrent acute pancreatitis includes all the risk of acute pancreatitis and often progresses to chronic pancreatitis with variable complications of chronic pain, exocrine insufficiency, diabetes, and pancreatic cancer. However, the great variability among individuals with RAP requires better precision in defining the risks, individual episodes, as well as their frequency, pathogenic pathways, and specific outcome measures for each of the systems affected by pancreatic inflammation. Because of disease complexity, few patients are similar enough for traditional studies and methods to conduct clinical trials with small sample sizes are required. The need for genetic testing, biomarker development, and better imaging methods was highlighted. Adaptive and N-of-one study designs, better endpoints, and outcome measures including patient-reported outcomes should considered early in developing future therapeutic trial design and include all stakeholders.

Relationship of Initial Pancreatic Enzyme Replacement Therapy Dose With Weight Gain in Infants With Cystic Fibrosis.

OBJECTIVE: The aim of the study is to test the hypothesis of a positive relationship between initial dose of pancreatic enzyme replacement therapy (PERT) in infants with cystic fibrosis (CF) and optimal weight gain over the first 2 years of life. METHODS: Using the CF Foundation Patient Registry, we identified 502 children born in 2010 and used multivariable models to compare as our primary analysis their 2-year changes in weight-for-age z score (WAZ) and as our secondary analysis weight-for-length percentile (W/L%) by initial PERT dose. We focused on initial dose without reference to subsequent changes in treatment to avoid confounding by indication (severity). RESULTS: Initial PERT dose demonstrated a linear relationship to change in WAZ and W/L% at age 2 years. An initial dose of >1500 lipase units/kg/largest meal resulted in a higher likelihood of attaining WAZ at 2 years at or above the birth WAZ (adjusted odds ratio [aOR] 1.87, 95% confidence interval [CI] 1.22-2.86) and at the top quartile for improvement over 2 years in WAZ (aOR 1.90, 95% CI 1.19-3.05). There was no correlation between initial PERT dose and weight at initial PERT encounter (P = 0.35). Findings were similar for W/L% and when the cohort was restricted to infants who began PERT in the first 3 months of life. CONCLUSIONS: Infants receiving higher initial PERT dose demonstrate better weight-related outcomes, as reflected by attainment of favorable changes in WAZ and W/L%, at age 2 years.

Less common etiologies of exocrine pancreatic insufficiency.

Exocrine pancreatic insufficiency (EPI), an important cause of maldigestion and malabsorption, results from primary pancreatic diseases or secondarily impaired exocrine pancreatic function. Besides cystic fibrosis and chronic pancreatitis, the most common etiologies of EPI, other causes of EPI include unresectable pancreatic cancer, metabolic diseases (diabetes); impaired hormonal stimulation of exocrine pancreatic secretion by cholecystokinin (CCK); celiac or inflammatory bowel disease (IBD) due to loss of intestinal brush border proteins; and gastrointestinal surgery (asynchrony between motor and secretory functions, impaired enteropancreatic feedback, and inadequate mixing of pancreatic secretions with food). This paper reviews such conditions that have less straightforward associations with EPI and examines the role of pancreatic enzyme replacement therapy (PERT). Relevant literature was identified by database searches. Most patients with inoperable pancreatic cancer develop EPI (66%-92%). EPI occurs in patients with type 1 (26%-57%) or type 2 diabetes (20%-36%) and is typically mild to moderate; by definition, all patients with type 3c (pancreatogenic) diabetes have EPI. EPI occurs in untreated celiac disease (4%-80%), but typically resolves on a gluten-free diet. EPI manifests in patients with IBD (14%-74%) and up to 100% of gastrointestinal surgery patients (47%-100%; dependent on surgical site). With the paucity of published studies on PERT use for these conditions, recommendations for or against PERT use remain ambiguous. The authors conclude that there is an urgent need to conduct robust clinical studies to understand the validity and nature of associations between EPI and medical conditions beyond those with proven mechanisms, and examine the potential role for PERT.

Pancreatic enzyme replacement therapy dosing and nutritional outcomes in children with cystic fibrosis.

OBJECTIVES: To utilize the Cystic Fibrosis Foundation Patient Registry to evaluate whether pancreatic enzyme dose is associated with better nutritional status as measured by average body mass index (BMI) percentile. STUDY DESIGN: A retrospective analysis of the Cystic Fibrosis Foundation Patient Registry from 2005-2008 was performed. The final analysis included 42 561 patient visits from 14 482 patients 2-20 years of age taking pancreatic enzyme replacement therapy from 179 programs. Cystic fibrosis care programs were assigned to quartiles based on adjusted mean patient BMI percentiles. Differences in median lipase dose between programs in the highest and lowest BMI quartiles were examined using a mixed effects model that adjusted for individual patient BMI, age, race, ethnicity, forced expiratory volume in 1 second percent, acid-blocker use, presence of Pseudomonas aeruginosa, nutritional supplement use, growth hormone use, and diagnosis of cystic fibrosis-related diabetes. RESULTS: A significant difference in median enzyme dose existed between the highest and lowest BMI quartiles. Multivariable analysis demonstrated the effect persisted after adjustment for covariates. Highest quartile programs had a median enzyme dose of 1755 lipase units/kg/meal compared with 1628 lipase units/kg/meal for lowest quartile programs. CONCLUSION: Patients attending US cystic fibrosis programs achieving highest nutritional outcomes, measured by mean BMI percentile, have higher enzyme dosing than those attending programs at lower performance levels. Further randomized clinical trials are necessary to determine the role of enzyme dose in improving nutritional outcomes.

Just a scary dream? A brief review of sleep terrors, nightmares, and rapid eye movement sleep behavior disorder.

The clinical spectrum of sleep disorders in children is broad, ranging from primary snoring and obstructive sleep apnea (OSA) syndrome to complex sleep-related behaviors and movement disorders. Although snoring and OSA typically receive significant attention and discussion, other biologically based sleep disorders are as common, if not more common, in children. A general pediatrician is frequently presented with the complaint of sleep talking, sleep walking, or abnormal movements during sleep. Even more alarming is the presentation of the child suddenly and explosively screaming during sleep. Such complaints fall under the category of parasomnias. Exclusive to sleep and wake-to-sleep transitions, these parasomnias include arousals with abnormal motor, behavioral, autonomic, or sensory symptoms. Parasomnias can be noticeably dissimilar in clinical manifestations, but most share biologic characteristics. Three parasomnias associated with loud vocalizations associated with sleep that can present to general practitioners include sleep terrors, nightmares, and rapid eye movement sleep behavior disorder (RBD). Although usually benign, these sleep disorders can be disruptive and even potentially dangerous to the patient and can often be threatening to quality of life. In this article, we describe the clinical features of some of these disorders and how to differentiate between their alarming presentations.

Successful use of plasmapheresis for granulomatosis with polyangiitis presenting as diffuse alveolar hemorrhage.

Diffuse alveolar hemorrhage (DAH) is uncommon in pediatric patients and is a rare presenting sign of granulomatosis with polyangiitis (GPA). We present the case a 14-year-old girl who presented with respiratory failure secondary to DAH as the initial presenting sign of GPA. Her clinical course improved after initiation of plasmapheresis therapy and she is now in clinical remission.

Sleep related expiratory obstructive apnea in children.

STUDY OBJECTIVES: We describe the respiratory, cardiac, and sleep-related characteristics of two types of sleep-related respiratory pauses in children that can fulfill current criteria of pathological apnea, but often seem to be benign: prolonged expiratory apnea (PEA) and post-sigh central apnea (PSCA). METHODS: All outpatient comprehensive overnight polysomnography completed on children without significant underlying medical conditions completed during an 18-month period were retrospectively reviewed for the presence of augmented breaths followed by a respiratory pause. Events were identified as a PEA or PSCA based on characteristic features. Physiologic parameters associated with the respiratory events were recorded and compared. RESULTS: Fifty-seven (29 PEA and 28 PEA) events were identified in 17 patients (8.5 ± 3.5 years old). Median durations of PEA and PSCA were not significantly different. For both PEA and PSCA, average heart rate (HR) during the augmented breath before the respiratory pause differed from lowest instantaneous HR during the first half of the pause. When compared to each other, the lowest instantaneous HR recorded in the first half of PEA was lower than that for PSCA (63.9 [59.41-68.3] vs 66.75 [61.7-80.75]) beats per min, p = 0.03. No PEA or PSCA event was associated with an oxygen desaturation more than 3% from baseline. CONCLUSION: PEA and PSCA have stereotypic HR changes and resemble pathologic apneas but appear to be benign. Clinical significance of PEA and PSCA is yet to be determined. Consistent recognition of the events is required, given their frequency of occurrence and potential for misclassification.

Successful prolonged use of recombinant human insulin-like growth factor-1 in a child with cystic fibrosis.

Growth failure is a common and complicated process in children with cystic fibrosis (CF). Growth hormone, which is becoming a more commonly used agent in such patients, has demonstrated beneficial effects aside from increased growth velocity. Recently, insulin-like growth factor-1 has gained significant attention in the understanding of growth failure in children with CF. We report the successful prolonged use of recombinant human insulin-like growth factor-1 in an adolescent boy with CF, who demonstrated significant clinical benefits from the therapy.