Risk Factors for Rapid Progression From Acute Recurrent to Chronic Pancreatitis in Children: Report From INSPPIRE

Abstract

Objective: The aim of the study was to determine the rate of progression from acute recurrent pancreatitis (ARP) to chronic pancreatitis (CP) in children and assess risk factors.

Study design: Data were collected from the INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE) cohort. Kaplan-Meier curves were constructed to calculate duration of progression from initial attack of acute pancreatitis (AP) to CP. Log-rank test was used to compare survival (nonprogression) probability distribution between groups. Cox proportional hazard regression models were fitted to obtain hazard ratio (with 95% confidence interval [CI]) of progression for each risk variable.

Results: Of 442 children, 251 had ARP and 191 had CP. The median time of progression from initial attack of AP to CP was 3.79 years. The progression was faster in those ages 6 years or older at the first episode of AP compared to those younger than 6 years (median time to CP: 2.91 vs 4.92 years; P = 0.01). Children with pathogenic PRSS1 variants progressed more rapidly to CP compared to children without PRSS1 variants (median time to CP: 2.52 vs 4.48 years; P = 0.003). Within 6 years after the initial AP attack, cumulative proportion with exocrine pancreatic insufficiency was 18.0% (95% CI: 12.4%, 25.6%); diabetes mellitus was 7.7% (95% CI: 4.2%, 14.1%).

Conclusions: Children with ARP rapidly progress to CP, exocrine pancreatic insufficiency, and diabetes. The progression to CP is faster in children who were 6 years or older at the first episode of AP or with pathogenic PRSS1 variants. The factors that affect the aggressive disease course in childhood warrant further investigation.

Figure 1.. Progression from ARP to CP in the INSPPIRE cohort.

(A) Kaplan-Meier curve (with 95% CI, dashed lines) for the outcome of progression to CP, with estimate of median time to progression of 3.79 (IQR: 1.11–8.46) years. (B) Comparison of Kaplan-Meier of CP progression between those with and without PRSS1 variant showing a significantly faster rate of progression to CP among those with PRSS1 variant with hazard ratio of progression of 1.68; 95% CI 1.22, 2.32; p=0.001). Median time of progression to CP was 2.52 [0.25–5.50] years vs 4.48 [1.25–8.87] years, respectively.

Figure 2.. Faster progression to CP in children with later onset disease.

(A) Kaplan-Meier curve of progression to CP showing children who had their first episode of AP at 6 years or older had a faster rate of progression to CP compared to those with first episode at age less than 6 years, with median time of progression of 2.91 [0.86–8.79] years vs 4.92 [1.91–8.46] years, respectively (hazard ratio 1.47; 95% CI: 1.08, 2.01; p=0.01) (B) Graph demonstrating children who had their first episode of AP at the age intervals 6 years or older had shorter median number of years to CP compared to children with first episode less than 3 years of age and between 3 – 5 years of age.

Figure 3.. Faster progression to EPI and diabetes mellitus in INSPPIRE cohort.

(A) Kaplan-Meier curve of progression to EPI after initial AP attack is shown. 6.6% (95% CI: 4.4%, 9.9%) were diagnosed with EPI within 1 year of initial AP attack; 9.4% (95% CI: 6.5%, 13.4%) within 2 years, there were diagnosed with EPI; 14.9% (95% CI: 10.5%, 20.9%) by 5 years. Within 6 years (through 12 years) from initial AP attack cumulative proportion with EPI was 18.0% (95% CI: 12.4%, 25.6%). (B) Kaplan-Meier curve of progression to diabetes mellitus after initial AP attack is shown. 2.1% (95% CI: 0.9%, 4.4%) were diagnosed with diabetes mellitus within 2 years of initial AP attack. Overall, 7.7% (95% CI: 4.2%, 14.1%) were diagnosed with diabetes mellitus within 6 years of initial AP attack (through the last follow-up).