The Pediatric Pouch Deserves Precision

Pediatric ulcerative colitis (UC) is characterized by a more severe presentation and aggressive disease course than adult-onset UC. Despite the development and widespread use of antitumor necrosis factor (TNF) agents, 13% to 14% of children with newly diagnosed UC will require colectomy within 5 years of diagnosis.^1–3 Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the preferred surgical intervention; however, inflammatory and structural complications of the pouch, such as pouchitis, are common and can lead to pouch failure. Although the characterization, natural history, diagnosis, and classification of pouch disorders in adults continue to be delineated,⁴ the pediatric pouch has largely been set to the side. Prior limited studies have found comparable rates between pediatric and adult pouches of pouchitis (30% to 67%) and pouch failure^5,6,7,8; however, pouch-related complications overall might be higher in children.⁸

In this issue of Inflammatory Bowel Diseases, 2 studies focus specifically on the pediatric pouch and bring to light 3 critical aspects of the pouch: (1) the evolving definitions of pouch complications, (2) the unique clinical context of pediatric IBD, and (3) the need for future research to improve pouch outcomes.

The majority of what is currently known about pediatric pouch outcomes is derived from single-center studies. Building upon a string of publications using claims data to provide a landscape of postsurgical outcomes in IBD, Cowherd et al applied a previously validated case-finding definition for pouchitis to children younger than 18 years old to attempt to establish a population-wide incidence of pediatric pouchitis.⁹ Patients with a preoperative diagnosis of UC, Current Procedural Terminology code for IPAA, International Classification of Diseases codes for pouchitis, or a prescription for ciprofloxacin or metronidazole within 2 years of IPAA were identified and classified as having pouchitis. The validation of this case-finding definition relied upon the interpretation of 2 IBD experts to verify the clinical diagnosis of pouchitis “based on clinical symptoms and response to therapy.”

The diagnosis and definition of pouchitis based on clinical symptoms are both common practices and comprise a significant proportion of the literature base. However, reliance upon clinical symptoms alone may lead to misattribution of stool frequency and stool urgency, among other symptoms, to the inflammatory state of the pouch, when the true etiology might be structural (such as pouch anastomotic leak) or functional (such as irritable pouch syndrome). Despite the limitations of claims data and the primarily symptom-based diagnosis of pouchitis, Cowherd et al confirmed 37 cases of pouchitis in 68 children who underwent IPAA from among the over 79 million individuals in the IQVIA Legacy PharMetrics Adjudicated Claims Data.⁹ This rate of 54% within 2 years of IPAA is consistent with prior single-center cohorts and most similar to the largest pediatric multicenter cohort study on pediatric pouch outcomes. In that study of 129 pediatric patients across 17 IBD centers, in which the symptom-based diagnosis of pouchitis was found in 44% of first episodes, the rate of pouchitis was 53% within 2 years of IPAA.⁵

In contrast, Runde et al defined pouchitis by endoscopic inflammation of the tip, proximal, or distal pouch and excluded subjects with clinical symptoms in the absence of endoscopic findings.¹⁰ They apply this definition to an extensive single-center cohort of endoscopic characterization of the pouch to determine pouch outcomes in children. Notably, a proportion of the patients in this cohort underwent endoscopic evaluation of the pouch while asymptomatic, as per the clinical practice of the provider, and it is implied that a portion of the pediatric patients had endoscopic pouchitis in the absence of clinical symptoms. Based upon this endoscopic definition of pouchitis, they identified 41 patients with pouchitis from 53 who underwent IPAA when younger than 19 years old, resulting in a rate of 77%.

It is imperative to delineate the definition of “pouchitis,” and these 2 studies alone illuminate a broad spectrum of phenotypes that may constitute disparate clinical implications. To address this lack of precision, the International Ileal Pouch Consortium (IIPC), through a rigorous consensus process, set forth a definition for pouchitis that includes both clinical and endoscopic factors.⁴ Setting this as the standard, future study on asymptomatic, endoscopically active pouch inflammation is crucial. We must also recognize that the classic “pouchitis” that relies upon clinical symptoms—and lacks endoscopic characterization—may represent a spectrum of pouch complications, including structural and functional disorders. Furthermore, true inflammatory “pouchitis” encompasses a spectrum of disease processes, ranging from acute to chronic pouchitis, from antibiotic-responsive to antibiotic-refractory pouchitis. Although this level of discrimination makes comparisons difficult in small cohorts, diagnostic precision is especially important in pediatrics, given a child’s vulnerable state with disease-related uncertainties, including growth and pubertal development, reproductive capacity, and psychosocial maturation.

Rates of pouchitis in children, however defined, have seemed comparable with those in adults, but Runde et al presented data here that reinforce the far more consistent pattern, that disease severity and complications are higher in pediatric IBD.¹⁰ Through Kaplan-Meier estimates of pouch survival probability, they found that children who underwent IPAA in the most recent decade (2010s) had lower pouch survival than children who underwent IPAA in 1990s/2000s and compared with adults who underwent IPAA overall (comparison group of 329 adults). Pouch survival was lower in children who received anti-TNF therapy precolectomy than children who did not; furthermore, pouch survival was lower in children who received anti-TNF precolectomy than adults with precolectomy anti-TNF use. Although anti-TNF use may indicate a more severe disease phenotype, the difference in pouch survival was not observed among adults with IPAA. Altogether, the authors contended that pouch survival is lower in children since the increased utilization of anti-TNFs over the last 16 years.

Other factors may contribute to pouch failure. It is notable that 70% (7 out of 10) of the children with pouch loss in the Runde et al study were characterized as having de novo Crohn’s disease.¹⁰ This cohort experienced a rate of pouch loss at 18.9%, higher than prior studies of 6% to 10%, some of which excluded de novo Crohn’s disease in analyses of pouch survival.^6,11,12 The proportion of children initially diagnosed with UC who later were found to have Crohn’s disease is higher than in adults. When this occurs after colectomy, it is difficult to discern whether the phenotype was Crohn’s colitis from inception or newly developed Crohn’s disease in the postoperative state. Cowherd et al found an ICD-9 conversion rate from UC precolectomy to Crohn’s disease post-IPAA of 9% within the 2 years⁹; in Runde et al, the rate of change to de novo Crohn’s was 38% over an average follow-up of almost 14 years.¹⁰ In a prior study, the rate of de novo Crohn’s disease was 25% among 56 children who underwent IPAA.¹³ Further study of children originally diagnosed with UC who later are diagnosed with Crohn’s disease is critical. Importantly, the diagnosis of Crohn’s disease of the pouch is sometimes misapplied (eg, pouch fistula is often due to structural complications and does not in itself reflect Crohn’s disease). To ensure accurate diagnosis, the IIPC has established a consensus characterization of these pouch disorders.⁴ The goal is for this to serve as the foundation for targeted treatment, which may include endoscopic or surgical intervention.

On a related note, the use of biologics was higher in children post-IPAA in Runde et al’s cohort, both when compared with children diagnosed with childhood-onset UC who underwent IPAA as adults and adult IPAA.¹⁰ This may reflect more frequent inflammatory disorders including de novo Crohn’s disease of the pediatric pouch. Combined with the observation that anti-TNF use precolectomy may portend lower pouch survival in the pediatric pouch, there are likely unique aspects of pediatric pouch physiology that remain to be elucidated. The clinical practice patterns of those caring for pediatric patients could also be a factor. An important limitation of this study, acknowledged by the authors, is that an endoscopic database at a referral center likely excludes clinical diagnoses with mild severity managed at local sites. Regardless, the pediatric pouch presents unique challenges.

One key area that was not rigorously evaluated in these 2 studies was the role of surgical factors in pouch outcomes. Although limited data was available in Runde et al, it was not a primary focus of the study.¹⁰ The stages of colectomy and IPAA surgery in children have bee\tn suspected to play a role in pouch complications; however, some evidence indicates that the number and type of stages are comparable without appreciable differences in pouch complications, potentially owing to the integration of pre-operative factors in surgical team decision-making and approach.¹⁴ Other surgical factors, such as laparoscopic vs open approaches or hand-sewn vs stapled anastomosis, may predict outcomes as well; however, personalized surgical care makes comparisons difficult without randomized clinical trials.¹⁵ In addition, the surgical technique of IPAA in children necessitates a degree of projected growth, both of the individual and pelvic structures. For example, many pediatric patients undergo a pull-through IPAA, and the retaining of peripouch fat may contribute to the distensibility of the pouch over time, which is itself a risk factor for pouchitis.¹⁶ Finally, the surgical case volume of the hospital and experience of the surgeon may play a role in pouch-related complications in children, including pouchitis,⁵ and the use of claims data may contribute to further understanding as it has for complications following colectomy in children.¹⁷

The significant burden of pouchitis, de novo Crohn’s disease, and pouch loss illuminated by these 2 studies provides impetus to establish a more clearly defined natural history of the pediatric pouch prospectively, including endoscopic evaluation. The disease spectrum of the pouch in children may mirror that in adults as outlined in the consensus guideline from the IIPC.⁴ Although the previous paradigm of monitoring clinical symptoms with reactive endoscopic evaluation may suffice in adult UC, the common change of pediatric UC to Crohn’s disease should guide us to pursue a proactive approach in children. A more precise characterization of pediatric pouch disorders will provide the basis to uncover pertinent risk factors, appropriate targets for prevention and, presently, more precise therapeutic interventions.

Acknowledgments

J.P. is supported by the Dan and Jill Wallen Family.

Conflicts of Interest

The authors have no financial disclosures or conflicts of interest.

References