Pediatric Longitudinal Cohort Study of Chronic Pancreatitis

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).

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 DEXA scan), fat soluble vitamin deficiencies (serum vitamin levels for A, D,
E, Pro Time/International Normalised Ratio and Partial Thromboplastin Time for vitamin
K) and bone density (DEXA scan) in children with ARP or CP at the time of enrollment and
annually thereafter.

The investigators will identify patients 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 patients 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 patient will be able to give either
blood or saliva. Six ml of blood will be collected from patients 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.
Patient 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 patient 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.

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.