Once considered an uncommon disease, the incidence of pediatric acute pancreatitis (AP) has increased over the last 10–20 years, affecting approximately 1 in 10,000 children.1–7 Acute recurrent pancreatitis (ARP), characterized as two or more discrete episodes of acute pancreatitis, is reported in 15–35% of children following an initial occurrence of AP.1,2,4,8 Chronic pancreatitis (CP), in which children have imaging or functional evidence of irreversible pancreatic damage,9 is estimated to have an incidence of ~2 per 100,000 children per year.7,10 Both ARP and CP are associated with significant disease burden.11,12 Children experience frequent abdominal pain, emergency room (ER) visits, and hospitalizations. They usually undergo numerous endoscopic and surgical procedures. INSPPIRE is the first multicenter, multidisciplinary collaboration that seeks to examine pancreatitis in children.9,11–17 and to define the characteristics and sequelae associated with ARP or CP.18–22

 

The INternational Study Group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE) Consortium was formed to systematically characterize ARP and CP in childhood and address the knowledge gap in pediatric pancreatitis. The work done through INSPPIRE Consortium, funded by a National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), R21 grant, has led to the establishment of the first multicenter pediatric pancreatitis cohort study, the INSPPIRE cohort.14 The INSPPIRE Study has enrolled over 500 children with ARP or CP and begun to define the risk factors, natural history, disease burden, and outcome of pediatric ARP and CP.9,11–17,23–27 INSPPIRE has provided a much more detailed cross-sectional assessment of pediatric ARP and CP than was previously available, but its longitudinal contribution was limited. Data on disease progression and treatment efficacy in children has so far remained largely retrospective. Importantly, the lack of patient data and understanding of disease pathogenesis make it difficult to design and implement therapeutic trials in children.

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Multiple barriers hinder advances in our understanding of pancreatitis in children. Although ARP and CP are more common than previously estimated, they are not common enough for single-center studies to provide definitive answers. Only through a prospective, longitudinal, and multi-center approach can we address the fundamental gaps in the knowledge of pediatric ARP and CP.

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In 2015, the INSPPIRE Consortium became a member of the Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer (CPDPC),28 funded by the NIDDK and the National Cancer Institute that led to forming the INSPPIRE 2 Cohort. In this report, we describe our efforts to build the INSPPIRE 2 cohort within CPDPC, as well as the rationale, study design, sample size, statistics. and future plans.

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Objectives and Hypothesis
The primary objectives of the INSPPIRE 2 study are (1) to comprehensively characterize the pediatric population with ARP and CP and (2) to determine predictors for early onset CP and its sequelae including disease burden, exocrine pancreatic insufficiency (EPI), and diabetes. INSPPIRE 2 will provide a longitudinal cohort of well-phenotyped patients and biological samples to achieve these objectives and for future research defining the pathogenesis and testing novel therapies.

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We hypothesize that childhood-onset ARP follows a severe disease course with rapid progression to CP and early development of complications including persistent abdominal pain, growth and nutritional disturbances, EPI, glycemic abnormalities, diabetes, repeated hospitalizations and procedures, all of which result in socioeconomic burden and impaired quality of life. We also hypothesize that specific risk factors predispose children to early progression from ARP to CP, and specific risk factors predispose children to CP sequelae and high disease burden. Furthermore, the prospective collection of biological samples from children with ARP and CP will provide a framework to develop biomarkers for early diagnosis of CP in children with ARP and identify disease predictors for its complications (i.e. chronic abdominal pain, growth and nutritional disturbances, EPI, glycemic abnormalities, diabetes).

Transition From INSPPIRE to INSPPIRE 2 Cohort
Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer is a National Institutes of Health (NIH) U01 funded consortium that aims to comprehensively characterize clinical, epidemiological, and biological aspects of patients with CP (including those with ARP) and to gain insight into the pathophysiology of CP and its sequelae. Sequelae of interest include chronic abdominal pain, EPI, type 3 diabetes mellitus (T3cDM) and pancreatic cancer, in both pediatric and adult populations.28 The pediatric aspect of CPDPC began as a Pancreatic Interest Group (PIG) in 2009, which later coalesced as the INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE) group.14 INSPPIRE started as a consortium of 14 institutions that grew to 18, including international collaborators (Australia, Israel, and Canada). The goals of INSPPIRE were to: i) collect longitudinal data and DNA samples from carefully phenotyped children with ARP or CP; ii) create a network of pediatric centers to perform prospective clinical studies; iii) define risk factors that predispose children to ARP and the development of CP, EPI, and T3cDM; and iv) develop diagnostic or therapeutic guidelines for pediatric ARP and CP through prospective studies. To achieve these goals, we first developed definitions of AP, ARP, and CP and surveyed practice trends at INSPPIRE sites.9 This was followed by the formation of a prospective database and sample repository for children with ARP or CP.14

 

In 2015, INSPPIRE joined CPDPC, and a new cohort of pediatric ARP or CP was conceptualized. This cohort, called INSPPIRE 2, was planned to build on the structure of and lessons learned from INSPPIRE, add more pediatric sites, change the governance structure, and expand to include nutritional and developmental outcomes and quality of life assessment tools to monitor pain, emotions, and behavior.

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INSPPIRE 2 Study Design
INSPPIRE 2 is a prospective, observational cohort study. A total of 860 patients under 18 years of age with ARP or CP will be enrolled, including as many of the >500 patients from the INSPPIRE database as possible.14 Patient questionnaires and physician surveys will be applied at the time of enrollment and annually thereafter. After turning 18 years of age, patients must sign an Institutional Review Board (IRB)-approved consent form to continue the study. Data will be collected on several domains including etiology, disease course, medical interventions, and surgical interventions.

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INSPPIRE 2 Governance Structure and Participating Centers
With the establishment of U01 funding, MD Anderson became the Coordinating and Data Management Center (CDMC) of the CPDPC, assuming the functions of the University of Iowa for data management, governance, and analysis. The INSPPIRE group added 4 additional sites after joining CPDPC, mainly by including the pediatric sites associated with participating adult sites. University of Iowa continues to oversee INSPPIRE 2 and houses the INSPPIRE principle investigator (PI) (A.U.), a clinical study coordinator and grant manager for study support and oversight in all 22 sites, overall research direction of the INSPPIRE 2 and subcontracting of most sites (except University of Indiana, Stanford, and Cedars-Sinai subcontracted by CDMC). The participating INSPPIRE 2 centers are listed in Table 1. INSPPIRE 2’s effort requires significant logistical support. Each center obtains IRB approval locally and establishes sub-contracts with University of Iowa (18) or CDMC (3), all overseen by NIDDK. This process is complex, but ensures that the study design, data collection methods, and other study elements are robust and widely applicable.