Infliximab Rescue Therapy in Pediatric Severe Colitis.

INTRODUCTION: Clinical remission has been achieved with infliximab in patients with refractory ulcerative colitis (UC). However, there is conflicting data regarding its effectiveness as rescue therapy in adult acute severe colitis. Furthermore, pediatric inflammatory bowel disease (IBD) is associated with more severe disease that may be less amenable to attempted rescue. We reviewed our experience and outcomes with pediatric severe colitis after attempted inpatient rescue with infliximab. METHODS: A single-institution, retrospective review was conducted of pediatric patients with UC or indeterminate colitis who received inpatient rescue infliximab therapy from 1/2000 to 1/2019. Rescue infliximab therapy was considered if a child failed non-biologic therapy or progressed to fulminant or toxic colitis. Primary outcome was failed therapy resulting in colectomy. A p-value of <0.05 determined significance. RESULTS: Thirty patients met inclusion criteria. The median age at administration of rescue infliximab treatment was 14 years [IQR 13,17]. Rescue therapy with infliximab was successful in 33% (n = 10), while 67% (n = 20) underwent colectomy. Children on maintenance steroids were less likely to be successfully rescued with infliximab and require colectomy (p = 0.03). Children requiring colectomy had a longer hospital stay (p = 0.03), more abdominal radiographs (p = 0.01), and were on a longer duration of antibiotics (p = <0.01) compared to children who were successfully rescued with infliximab. There was no difference in baseline vital signs or laboratory abnormalities between the two groups. CONCLUSION: In severe acute ulcerative or indeterminate colitis cases where infliximab has not been previously used, rescue infliximab can be used to avoid colectomy but has a high failure rate. LEVEL OF EVIDENCE: IV. TYPE OF STUDY: Retrospective study.

Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: A Pragmatic Randomized Trial.

BACKGROUND & AIMS: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. METHODS: Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. RESULTS: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. CONCLUSIONS: Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. CLINICALTRIALS: gov, Number: NCT02772965.

Use, Durability, and Risks for Discontinuation of Initial and Subsequent Biologics in a Large Pediatric-Onset IBD Cohort.

BACKGROUND: Biologic medications are recommended for treatment of moderately-to-severely active Crohn disease (CD) or ulcerative colitis (UC) in children. However, many patients require sequential biologic treatment because of nonresponse or loss of response to the initial biologic. METHODS: We analyzed pediatric inflammatory bowel disease (IBD) data from the ImproveCareNow Network registry between May 2006 and September 2016, including time to biologic initiation, choice of first subsequent biologics, biologic durability, and reasons for discontinuation. RESULTS: Of 17,649 patients with IBD [CD: 12,410 (70%); UC: 5239 (30%)], 7585 (43%) were treated with a biologic agent before age 18 (CD: 50%; UC: 25%). Biologic treatment was more likely for CD than UC (odds ratio, 3.0; 95% CI: 2.8-3.2; P < 0.0001). First biologic agents for all patients were anti-tumor necrosis factor agents (88% infliximab, 12% adalimumab). Probability of remaining on the first biologic was significantly higher in CD than UC ( P < 0.0001). First biologics were discontinued because of loss of response (39%), intolerance (23%), and nonresponse (19%). In univariate analysis, factors associated with discontinuation of first and/or second biologics in CD include colonic-only disease, corticosteroid use, upper gastrointestinal tract involvement, and clinical and biochemical markers of severe disease. Biologic durability improved with later induction date. CONCLUSIONS: Treatment with biologic medications is common in pediatric IBD. Patients with CD are more likely to receive biologics, receive biologics earlier in disease course, and remain on the first biologic longer than patients with UC. Multiple factors may predict biologic durability in children with IBD.

Implementing a Novel Quality Improvement-Based Approach to Data Quality Monitoring and Enhancement in a Multipurpose Clinical Registry.

OBJECTIVE: To implement a quality improvement based system to measure and improve data quality in an observational clinical registry to support a Learning Healthcare System. DATA SOURCE: ImproveCareNow Network registry, which as of September 2019 contained data from 314,250 visits of 43,305 pediatric Inflammatory Bowel Disease (IBD) patients at 109 participating care centers. STUDY DESIGN: The impact of data quality improvement support to care centers was evaluated using statistical process control methodology. Data quality measures were defined, performance feedback of those measures using statistical process control charts was implemented, and reports that identified data items not following data quality checks were developed to enable centers to monitor and improve the quality of their data. PRINCIPAL FINDINGS: There was a pattern of improvement across measures of data quality. The proportion of visits with complete critical data increased from 72 percent to 82 percent. The percent of registered patients improved from 59 percent to 83 percent. Of three additional measures of data consistency and timeliness, one improved performance from 42 percent to 63 percent. Performance declined on one measure due to changes in network documentation practices and maturation. There was variation among care centers in data quality. CONCLUSIONS: A quality improvement based approach to data quality monitoring and improvement is feasible and effective.

Health-Related Quality of Life Predicts Psychology Referral in Youth with Inflammatory Bowel Disease.

PURPOSE: The current study sought to explore psychosocial data gathered from routine screening within an interdisciplinary IBD program, with two-fold aims: 1) to examine parent-child agreement across health-related quality of life domains and 2) to evaluate the differential predictive value of child and parent ratings of health-related quality of life domains on referrals for psychological services. DESIGN AND METHODS: A convenience sample of 92 youth (ages 8-18) and their parents completed the Pediatric Quality of Life Inventory. RESULTS: Children and parents showed moderate to good agreement across health-related quality of life domains. Additionally, regression analyses revealed that child and parent-proxy reports of emotional difficulties, parent report of school difficulties, and child report of physical symptoms were significantly predictive of psychology referral status. CONCLUSIONS: Study findings suggest moderate to good agreement among child and parent-proxy reporters and support the shared value of both child and parent ratings of health-related quality of life in predicting psychology referrals in youth with IBD. PRACTICE IMPLICATIONS: Routine psychosocial screening among youth with IBD can promote the early identification of emotional and behavioral needs, and family receipt of appropriate, evidence-based intervention.

Practice survey: adherence monitoring and intervention in pediatric gastroenterology and hepatology.

PURPOSE: Despite significant medication nonadherence rates among youth with pediatric gastroenterology and hepatology disorders, little is known about current adherence practices in pediatric gastroenterology care. This study summarizes current practices surrounding adherence monitoring and intervention in pediatric gastrointestinal (GI) and hepatologic care in the USA. PARTICIPANTS AND METHODS: One hundred and fifty-four pediatric GI providers completed an online survey designed to examine current practices surrounding adherence monitoring and intervention, specific strategies used to monitor and treat poor adherence, and the barriers currently experienced in relation to adherence monitoring and intervention. RESULTS: Practices varied greatly in terms of when and how patient adherence is monitored and by whom; however, physicians and nursing professionals take primary responsibility for adherence monitoring. Approximately 25% utilize screeners to assess adherence, and most participants use patient and caregiver reports as a primary measure of adherence. Most participants rated their level of adherence monitoring and intervention as fair to poor. While most participants perceive adherence monitoring to be very important in clinical practice, only 20.8% perceive being able to significantly modify patient adherence. CONCLUSION: There exists great variability in adherence monitoring and intervention practices across pediatric GI providers. Greater understanding of current adherence practices can inform future clinical efforts.

Investigation of potential early Histologic markers of pediatric inflammatory bowel disease.

BACKGROUND: Early manifestations of pediatric inflammatory bowel disease (IBD) can be relatively nonspecific. Initial mucosal biopsies may not be conclusive, delaying the diagnosis until subsequent biopsies demonstrate typical histologic features of IBD. We hypothesized that certain inflammatory cell types may be utilized as early histologic indicators of IBD in children. METHODS: A retrospective analysis compared histologic findings from initially inconclusive or negative endoscopic studies in 22 patients who were subsequently diagnosed with IBD (after diagnostic endoscopy) to those of 20 comparison patients with functional abdominal pain matched for age, gender, and study type. A pediatric pathologist, blinded to study group, reviewed biopsies for histologic abnormalities. Eosinophil densities were obtained from the stomach, duodenum, and rectosigmoid areas. Immunohistochemistry (IHC) staining for tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-9 (MMP-9) was performed on the stomach and rectosigmoid areas. RESULTS: Gastritis and colonic crypt distortion were present in the IBD group at a greater rate (61 % vs. 22 %, p = 0.020; 34 % vs. 4 %, p = 0.008, respectively). Peak and mean eosinophil densities in the rectosigmoid area were greater in the IBD group (17.0/hpf vs. 5.0/hpf, p = 0.0063; 12.3/hpf vs. 4.2/hpf, p = 0.0106, respectively). TNF-α and MMP-9 staining did not reveal any significant differences. CONCLUSIONS: Our data suggests that significantly greater inflammation in the stomach, crypt distortion in the colon, and eosinophilia in the rectosigmoid distinguished the IBD group from the comparison group at the time of the initial endoscopic evaluation.

Molecular diagnosis of infantile onset inflammatory bowel disease by exome sequencing.

Pediatric-onset inflammatory bowel disease (IBD) is known to be associated with severe disease, poor response to therapy, and increased morbidity and mortality. We conducted exome sequencing of two brothers from a non-consanguineous relationship who presented before the age of one with severe infantile-onset IBD, failure to thrive, skin rash, and perirectal abscesses refractory to medical management. We examined the variants discovered in all known IBD-associated and primary immunodeficiency genes in both siblings. The siblings were identified to harbor compound heterozygous mutations in IL10RA (c.784C>T, p.Arg262Cys; c.349C>T, p.Arg117Cys). Upon molecular diagnosis, the proband underwent successful hematopoietic stem cell transplantation and demonstrated marked clinical improvement of all IBD-associated clinical symptoms. Exome sequencing can be an effective tool to aid in the molecular diagnosis of pediatric-onset IBD. We provide additional evidence of the safety and benefit of HSCT for patients with IBD due to mutations in the IL10RA gene.

Pediatric Crohn disease presenting as appendicitis: differentiating features from typical appendicitis.

BACKGROUND: The initial presentation of Crohn disease (CD) may mimic acute appendicitis, and preoperative clues may aid in recognizing patients at risk for CD. METHODS: A retrospective case control study of patients presenting over 10 years compared control patients with appendicitis versus patients presenting with appendicitis who ultimately developed CD. We matched 10 patients of the same age, gender, and perforated versus nonperforated appendicitis status for each of the CD patients. Demographic, laboratory, and clinical data were compared. Additionally, appendectomy specimens of CD patients were genotyped for common NOD2 (nucleotide-binding oligomerization domain-containing protein 2) mutations. RESULTS: Of 2718 patients treated for appendicitis, 8 subsequently developed CD. Compared to the matched controls, CD patients were found to have lower hemoglobin (10.4 + 1.0 vs. 13.3 + 0.2, p < 0.0001) and mean corpuscular volume (MCV) (72.5 + 3.4 vs. 84.1 + 0.5, p < 0.0001) values, and higher platelets values (444.8 + 42.2 vs. 275.6 + 8.0, p < 0.0001) at initial presentation. Anthropometric z-scores, length of stay, and antibiotic therapy duration did not significantly differ between groups. The NOD2 mutation frequency (25%) was consistent with the currently described CD population. CONCLUSIONS: Preoperative findings of a low hemoglobin level and MCV count, and a high platelet count in a child presenting with appendicitis warrant further evaluation for CD, as prompt diagnosis allows for optimal treatment and quality of life for these patients.

Variation in Antibiotic Use for Children Hospitalized With Inflammatory Bowel Disease Exacerbation: A Multicenter Validation Study.

BACKGROUND: Antibiotics are often given for inflammatory bowel disease (IBD) exacerbations, but their use among pediatric inpatients has not been assessed. We aimed to validate administrative data for identifying hospitalizations for IBD exacerbation and to characterize antibiotic use for IBD exacerbations across children's hospitals. METHODS: To validate administrative data for identifying IBD exacerbation, we reviewed charts of 409 patients with IBD at 3 US tertiary care children's hospitals. Using the case definition with optimal test characteristics, we identified 3450 children with 5063 hospitalizations for IBD exacerbation at 36 children's hospitals between January 1, 2007 and December 31, 2009, excluding those with diagnosis codes for specific bacterial infections. We estimated predicted and expected hospital-specific antibiotic utilization rates using mixed-effects logistic regression, adjusting for patient- and hospital-level factors. RESULTS: Administrative codes for receipt of intravenous steroids or endoscopy provided 79% positive predictive value and 71% sensitivity for identifying hospitalizations for IBD exacerbation. Antibiotics were administered for ≥2 of the first 3 hospital days during 40.7% of IBD exacerbations in US children's hospitals; however, the proportion of patients receiving antibiotics varied significantly across hospitals from 27% to 71% (P < .001), despite adjustment for several patient- and hospital-level variables. Among those given antibiotics, the 3 most common regimens were metronidazole alone (26.9%), metronidazole with ciprofloxacin (10.3%), and ampicillin with gentamicin and metronidazole (7.0%). CONCLUSIONS: Significant variability exists in antibiotic use for children hospitalized with IBD exacerbation, which is unexplained by disease severity or hospital volume. Further study should determine the optimal antibiotic therapy for this condition.

Occurrence of Crohn's disease in children after total colectomy for ulcerative colitis.

BACKGROUND: Colectomy is the definitive treatment for ulcerative colitis (UC) to remove the inflammatory burden. Crohn's disease, however, can affect any portion of the bowel with a propensity to involve the terminal ileum. In some patients with fulminant colitis, distinction between the two is imperfect. Manifestations of Crohn's after colectomy can be devastating because the ileum is needed for restoration of continuity. There is currently little information in the pediatric literature addressing this concern. Therefore, we reviewed all of our patients who underwent colectomy for inflammatory bowel disease to evaluate the risk of subsequent Crohn's manifestations and to document the outcomes. METHODS: A two-center retrospective review of children who underwent colectomy for IBD from January 2000 to July 2010 was performed. Demographic, diagnostic, management, and outcome variables were recorded. RESULTS: We identified 70 patients who underwent colectomy for UC. The mean age at diagnosis was 12 y ± 7 y, and 59% were female. Clinical diagnosis prior to colectomy was UC in 90%, and indeterminate colitis in 10%. There was discordance between clinical and pathologic diagnosis in five patients, two patients were clinically diagnosed with UC but had an indeterminate biopsy, and three patients were clinically diagnosed as indeterminate colitis with a biopsy confirming UC. Indications for colectomy were refractory bleeding in 63%, failure of medical treatment in 28%, toxic megacolon in 6%, and perforation in 3%. A restorative pouch was created after colectomy in 46% using a two-stage approach while, 53% were managed with an initial colectomy and three-stage approach. In one patient, Crohn's was intraoperatively diagnosed from the operative colectomy specimen. This patient had a clinical diagnosis of UC with concordant biopsy prior to surgery. After total abdominal colectomy, 68 patients went on to ileal pouch anal anastomosis by either a two-stage or three-stage approach. In these patients, nine (13%) had a change in their diagnosis to Crohn's after reconstruction. Crohn's complications requiring an operation consisted of two patients with anastomotic dilations, four patients with fistulotomies, and one patient with perianal abscess drainage procedures. CONCLUSIONS: In the children studied, 13% had a diagnostic change to Crohn's disease, and 13% were diagnosed with Crohn's after ileal pouch-anal anastomosis (IPAA). In patients with IPAA and Crohn's, there were more operative interventions for perianal disease.