Pediatric Longitudinal Cohort Study of Chronic Pancreatitis
Pediatric Longitudinal Cohort Study of Chronic Pancreatitis
The investigators will enroll a total of 628 patients under 18 years of age with ARP or CP.
 Included in the total are the 357patients in the INSPPIRE 1 database who are planned to be
 reenrolled under this protocol over the next 4 years. Patient questionnaires and physician
 surveys will be applied at the time of enrollment and annually thereafter as long as
 possible. At the first study visit after turning 18 years of age, the patient will sign the
 informed consent to continue in the study. Specifically, the investigators will define the
 demographics of the pediatric ARP and CP cohort, describe risk factors, presence of family
 history of acute and chronic pancreatitis, diabetes and pancreatic cancer and assess disease
 burden and sequelae.
Disease Burden Pain. The pattern of the pain (constant versus episodic), its frequency,
 duration, visits to the emergency room or hospitalizations for pain, impact of pain on
 quality of life will be recorded in questionnaires. The intensity of the pain will be
 measured at enrollment, during an attack and annually using FACES Pain Scale-Revised, a
 self-report questionnaire validated for children >4 y/o. The names, dosing and frequency of
 medications taken for pain will also be queried.

 Health-Related Quality of Life (HRQOL). An age-specific instrument validated for United
 States children will be used to measure HRQOL at enrollment and annually thereafter. Parents
 of children 5-18 years old will complete Child Health Questionnaire Parent Form 50 questions
 (CHQ PF-50). Children >10 years old will answer Child Health Questionnaire Child Form 87
 questions (CHQ-87). Adults >18 years old will not complete a health-related questionnaire.
 These questionnaires capture physical functioning, social, emotional, physical and behavioral
 limitations, bodily pain, general behavior, mental health, self-esteem, general health
 perceptions, change in health and parental emotional impact.

 Depression and anxiety. Depression and anxiety are strong predictors of chronic pain and
 pain-related disability in children, but it is not known whether this applies to children
 with ARP or CP. The investigators will assess for depression and anxiety in the INSPPIRE
 cohort at the time of enrollment and annually thereafter. The investigators will utilize the
 Child Behavioral Checklist (CBCL), one of the most widely-used standardized measures in child
 psychology for evaluating maladaptive behavioral and emotional problems in preschool subjects
 aged 1½ to 5 years and in school-age subjects between the ages of 6 and 18. For preschool-age
 children, the CBCL/1½-5 (completed by parents or surrogates) will be used. For school-age
 children 6-18 y/o, the investigators will utilize CBCL/6-18 y/o (completed by parents or
 surrogates). Children who are 11-18 y/o will answer a self-report questionnaire (Youth-Self
 Report Form or YSR/11-18). CBCL assesses internalizing (i.e., anxious, depressive, and over
 controlled) and externalizing (i.e., aggressive, hyperactive, noncompliant, and
 undercontrolled) behaviors. Adults >18 years old will not complete a behavioral checklist.

 Patients/parents will spend approximately 2 hours answering questionnaires; their time will
 be compensated at $50 per visit. Patients will be enrolled during clinic visit as outpatient
 or as an inpatient. Alternatively, questionnaires can be applied over the phone or completed
 at home and returned via mail if the patient is unable to travel. Self-addressed stamped
 envelopes will be given to the patient/parent as needed for returning the questionnaires.

 Disease Sequelae

 The presence of exocrine pancreatic insufficiency and glucose intolerance/diabetes will be
 monitored at the time of enrollment and annually thereafter. Monitoring will include
 specifically:

 1. Exocrine pancreatic insufficiency: defined as the presence of abnormal fecal elastase (<
 100 ug/ g stool on 2 separate samples ≥ 1 month apart) or abnormal serum trypsin or
 serum trypsinogen.

 2. Diabetes or prediabetes: Monitoring for diabetes in our cohort will include once yearly
 assessments with fasting glucose (diabetes range if ≥ 126 mg/dL), HbA1c (abnormal if >6;
 diabetic if >6.5%) and oral glucose tolerance test (OGTT). For OGTT, 1.75 grams/kg of
 standard glucose beverage (glucola, maximum 75 grams) will be consumed within 10 minutes
 at time 0. Glucose will be drawn prior to the beverage and at time 120 minutes. From
 this test, glycemic status will be defined as: (1) normal glucose tolerance (NGT,
 fasting glucose <100 mg/dL, 2 hour <140 mg/dL); (2) pre-diabetic based on impaired
 fasting glucose (IFG, fasting glucose 100-125 mg/dL) and/or impaired glucose tolerance
 (IGT, 2 hour glucose 140-199 mg/dL); or (3) diabetic (DM, fasting glucose >126 mg/dL or
 2 hour glucose >200 mg/dL).

 3. Nutritional status including micronutrient deficiency: To determine the nutritional
 sequelae of ARP or CP in children, the investigators will assess for
 malnutrition/obesity (weight, height, BMI, z scores; body fat mass and lean mass as
 measured by DXA scan), fat soluble vitamin deficiencies (serum vitamin levels for A, D,
 and E and bone density (DXA scan) in children with ARP or CP at the time of enrollment
 and annually thereafter.

 The investigators will identify subjects within our cohort that presented with acute
 recurrent pancreatitis episodes, normal exocrine and endocrine pancreas function and normal
 pancreas imaging without any signs of chronicity (ARP cohort). The investigators will
 identify the development of CP on an annual basis as long as possible, as well as development
 of sequelae and disease burden as listed above.

 Prospective Registry

 The investigators will develop a database of children with ARP and CP. This will provide a
 cohort of well-phenotyped subjects for future studies targeting pathogenesis and novel
 therapies. The investigators will establish a process by which investigators outside of the
 consortium may have access to the data and biospecimens.

 At enrollment, via the informed consent, subjects will choose whether or not to allow use of
 their biological samples for this study, future research, genetic analysis, genetic analysis
 for future research, and any type of future research. They will also choose whether or not we
 may keep their name and personal information in a registry to allow us to contact them for
 other future research.

 BIOSPECIMEN COLLECTION

 Sample collection for deoxyribonucleic acid (DNA): The subject will be able to give either
 blood or saliva. Six ml of blood will be collected from subjects in an
 ethylenediaminetetraacetic acid tube or 2 ml saliva samples in Oragene DNA collection kits
 then labeled with the barcoded specimen labels provided by the Consortium for the Study of
 Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) Coordinating Center. The
 specimen labels provided by CPDPC include a specimen identification (ID) number and barcode.
 Subject identifiers (for example names or initials) are not included on the labels. Before
 shipping the specimens to the central repository the specimen ID number from the label will
 be connected to the patient information in the CPDPC's secure IIMS Specimen Manager system.
 After the specimen ID number is linked to the subject in the CPDPC system the samples will be
 submitted to the central repository for the study via overnight courier. The central
 repository for DNA will be at the University of Iowa. The central repository at Iowa will not
 have access to the link that connects to the patient's personal identifiers in the Integrated
 Information Management System (IIMS). The central repository will log receipt of the
 specimens into the CPDPC IIMS Specimen Manager system using the specimen ID from the labeled
 vials. The central repository will process the specimens into aliquots for the extraction of
 genomic DNA following the CPDPC specimen processing described in the appendices. The aliquots
 will be labeled with CPDPC supplied labels and stored in a freezer at -80 degree Centigrade.
 The CPDPC aliquots labels contain barcodes and specimen ID numbers that do not link the
 aliquots to each other. The only link to the subject information resides in the secured
 database at the CPDPC coordinating and data management center. The central repository
 laboratory staff and the study researchers do not have access to this link. At the end of the
 study the specimens stored in the central repository at Iowa will be transferred to a central
 repository at National Institute of Diabetes and Digestive and Kidney Diseases.

 Urine collection for bio-markers: To be completed only at sites identified by the lead site
 to collect urine samples. Not all sites will be collecting urine. See Appendix 14.27 for
 collection and processing instructions. The subject will be instructed to collect a minimum
 of 50 mL clean-catch urine sample. A dipstick urine analysis will be performed immediately
 after urine collection. Urine samples will then be kept on wet ice or refrigerated until
 processed. Samples will be processed within 4 hours of collection. Samples will be labeled
 with the barcoded specimen labels provided by the CPDPC Coordinating Center. The specimen
 labels provided by CPDPC include a specimen ID number and barcode. Subject identifiers (for
 example names or initials) are not included on the labels. Before shipping the specimens to
 the central repository the specimen ID number from the label will be connected to the subject
 information in the CPDPC's secure IIMS Specimen Manager system. After processing, samples
 will be frozen at -80ºC. The urine processing log sheet will be completed. Samples will be
 stored and batch shipped to the Central repository at University of Iowa annually. The
 central repository will log receipt of the specimens into the CPDPC IIMs Specimen Manager
 system using the specimen ID from the labeled vials. The central repository at University of
 Iowa will not have access to the link that connects the subject's personal identifiers in the
 IIMS system. The central repository will log receipt of the specimens into the CPDPC IIMS
 Specimen Manager system using the specimen ID from the labeled vials. The CPDPC aliquots
 labels contain barcodes and specimen ID numbers that do not link the aliquots to each other.
 The only link to the subject information resides in the secured database at the CPDPC
 coordinating and data management center. The central repository laboratory staff and the
 study researchers do not have access to this link. At the end of the study the specimens
 stored in the central repository at Iowa will be transferred to a central repository at
 NIDDK.
Inclusion Criteria:

 1. All patients/parents must sign an informed consent and/or assent indicating that they
 are aware of the investigational nature of this study.

 2 Patients/parents must have signed an authorization for the release of their or their
 child's protected health information.

 3 All children providing samples should fit the ARP or CP inclusion criteria defined below.

 4 All children must be under 18 years of age at the time of enrollment.

 Acute pancreatitis (AP): AP is defined as requiring 2 of the following:

 1. Abdominal pain compatible with AP,

 2. Serum amylase and/or lipase values ≥3 times upper limits of normal,

 3. Imaging findings of AP, such as gland enlargement, acute inflammatory changes, and
 fluid collections.

 ARP is defined as:

 At least 2 episodes of acute pancreatitis with complete resolution of pain and a >1 month
 pain-free interval between episodes.

 Chronic Pancreatitis:

 Children with at least:

 1. One irreversible structural change* in the pancreas with or without abdominal pain +/-
 exocrine pancreatic insufficiency +/- diabetes.

 *irreversible structural changes:

 -  Ductal calculi, dilated side branches, parenchymal calcifications found in any imaging
 (abdominal ultrasound (abd US), magnetic resonance imaging/magnetic resonance
 cholangiopancreatography (MRI/MRCP), computerized tomography (CT), endoscopic
 retrograde cholangiopancreatography (ERCP), endoscopic US (EUS).

 -  Ductal obstruction or stricture/dilatation/irregularities that are persistent (for >2
 months) on any imaging.

 -  Parenchymal atrophy, irregular contour, accentuated lobular architecture, cavities
 alone are not diagnostic findings for CP.

 -  Surgical or pancreatic biopsy specimen demonstrating histopathologic features
 compatible with CP (acinar atrophy, fibrosis, protein plugs, infiltration with
 lymphocytes, plasma cells, macrophages).

 Exclusion Criteria:

 -  Patients must not have any significant medical illnesses that in the investigator's
 opinion cannot be adequately controlled with appropriate therapy or would compromise
 the patient's ability to tolerate study interventions.