LONG-TERM DISEASE PROGRESSION IN PEDIATRIC PANCREATITIS: A REPORT FROM INSPPIRE

INTRODUCTION: Acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) are rare diseases in children. Prospective evaluation of progression to irreversible sequelae is currently lacking. This is the 1^st report of longitudinal, prospectively collected data that evaluates progression from ARP to CP and their end-stage sequelae in children.
METHODS: Longitudinal data from children with ARP or CP enrolled in INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE) cohorts were analyzed. Children were categorized as persistent ARP (pARP = ARP at INSPPIRE enrollment and through last follow-up; n=315), incident CP (iCP = ARP at enrollment, developed CP during follow-up; n=73), or prevalent CP (pCP = CP at enrollment; n=247). Time-to-sequelae was analyzed using Kaplan-Meier curves.
RESULTS: Of 635 children enrolled in INSPPIRE, 11% developed iCP, 50% were pARP, and 39% were pCP. Compared to children who started and remained ARP (pARP), those with iCP were more likely to have PRSS1 mutations (33% iCP vs. 13% pARP; p<0.001) and obstructive risk factors (35% iCP vs. 19% pARP; p<0.001), but did not differ by sex, race, ethnicity, CFTR or SPINK1 prevalence. Children with iCP averaged more lifetime acute pancreatitis (AP) attacks (mean 6.3±3.4) than those with pARP (4.2±2.8; p<0.001) but did not differ in age at 1^st AP attack.
Time between 1^st AP attack and CP diagnosis was significantly shorter in pCP (20±27 months), which was retrospectively reported at enrollment, than in iCP (38±31 months; p<0.0001), which was prospectively tracked. Children with iCP were slightly older at CP diagnosis (11.6±4.5 years) than pCP (10.6±4.1 years; p<0.0001).
Amongst children with ARP at enrollment, 32% developed exocrine pancreatic insufficiency (EPI) during follow-up, including 11% with pARP, but 47% with iCP. Mean months from 1^st AP attack to EPI diagnosis was slightly longer in those with iCP (39±35) than with pCP (32±35; p=<0.0001, FIGURE 1). Amongst all children with CP, 50% had EPI by 15 years of age, a mean of 5.5 years after 1^st AP attack.
Amongst children with ARP at enrollment, 13% developed diabetes mellitus (DM), 10% with pARP, but 28% with iCP (FIGURE 2). Amongst all children with CP, 50% had DM by 14 years of age, a mean of 11 years after 1^st AP attack.
DISCUSSION: Children without PRSS1 mutations or obstructive risk factors, or who had fewer attacks of AP, were less likely to progress to CP in this long-term study, highlighting the importance of addressing recurrent pancreatitis episodes and underlying etiologies in children. Challenges remain to accurately diagnose and phenotype early CP and sequelae, as some children with ARP developed EPI or even DM. INSPPIRE would be an excellent cohort to study the biomarkers of pediatric pancreatitis disease progression and its sequelae.