Long-term teduglutide associated with improved response in pediatric short bowel syndrome-associated intestinal failure.

OBJECTIVES: Patients with short bowel syndrome-associated intestinal failure (SBS-IF) require long-term parenteral nutrition and/or intravenous fluids (PN/IV) to maintain fluid or nutritional balance. We report the long-term safety, efficacy, and predictors of response in pediatric patients with SBS-IF receiving teduglutide over 96 weeks. METHODS: This was a pooled, post hoc analysis of two open-label, long-term extension (LTE) studies (NCT02949362 and NCT02954458) in children with SBS-IF. Endpoints included treatment-emergent adverse events (TEAEs) and clinical response (≥20% reduction in PN/IV volume from baseline). A multivariable linear regression identified predictors of teduglutide response; the dependent variable was mean change in PN/IV volume at each visit over 96 weeks. RESULTS: Overall, 85 patients were analyzed; 78 patients received teduglutide in the parent and/or LTE studies (any teduglutide [TED] group), while seven patients did not receive teduglutide in either the parent or LTE studies. Most TEAEs were moderate or severe in intensity in both groups. By week 96, 82.1% of patients from the any TED group achieved a clinical response, with a mean fluid decrease of 30.1 mL/kg/day and an energy decrease of 21.6 kcal/kg/day. Colon-in-continuity, non-White race, older age at baseline, longer duration of teduglutide exposure, and increasing length of remaining small intestine were significantly associated with a reduction in mean PN/IV volume requirements. CONCLUSIONS: In pediatric patients with SBS-IF, teduglutide treatment resulted in long-term reductions in PN/IV requirements. The degree of PN/IV volume reduction depended on the duration of teduglutide exposure, underlying bowel anatomy, and demographics.

Red cell abnormalities characterized by ektacytometry in children with cholestasis.

BACKGROUND: Spur-cell anemia sometimes accompanies cholestasis. We postulated that even in the absence of spur-cells, cholestasis might alter red blood cell (RBC) osmotic fragility and deformability. Therefore, we assessed these RBC measures by ektacytometry in pediatric patients. METHODS: We conducted a single center, prospective, cross-sectional investigation of RBC membrane characteristics by ektacytometry in pediatric patients with intra- and extrahepatic cholestasis followed at Cincinnati Children's Hospital Medical Center. We measured red cell membrane fragility and deformability in 17 patients with cholestasis and 17 age-matched controls without cholestasis. RESULTS: Patients with cholestasis had decreased RBC osmotic fragility compared to controls, with a significant left shift in Omin, indicating increased RBC surface-to-volume ratio. One showed spur cell morphology. However, the other 16 had no spurring, indicating that ektacytometry is a sensitive method to detect RBC membrane abnormalities. Left shift of Omin positively correlated with serum conjugated bilirubin levels and even more negatively with serum vitamin E concentration. CONCLUSIONS: This study suggests that subclinical red blood cell membrane abnormalities exist in most pediatric patients with cholestasis, increasing risk for hemolysis when subjected to oxidative stress. Hence minimizing pro-oxidants exposure and maximizing antioxidant exposure is advisable for this group. GOV IDENTIFIER: NCT05582447 https://clinicaltrials.gov/ct2/show/NCT05582447?cond=Cholestasis&cntry=US&state=US%3AOH&city=Cincinnati&draw=2&rank=2 . IMPACT: Spur cell anemia due to decreased red cell osmotic fragility and decreased deformability has been reported among patients with cholestasis. Ektacytometry is a reliable, reproducible method to measure red cell osmotic fragility and deformability. Few data describe red cell osmotic fragility or deformability in patients with cholestasis who may or may not have spur cell anemia. Ektacytometry shows that red cell osmotic fragility and deformability are decreased in many children with cholestasis even when spur cell anemia has not yet occurred. Factors associated with decreased osmotic fragility include elevated serum bilirubin, elevated serum bile acids, and decreased serum vitamin E.

Pediatric Intestinal Transplantation Management and Outcomes.

Intestinal failure is the anatomic or functional loss of intestinal function below the minimum required to absorb nutrients to maintain health and growth. Parenteral nutrition is the main supportive therapy for children with intestinal failure, but if serious complications develop, intestinal transplantation may be needed to sustain life. Referral to a multidisciplinary intestinal rehabilitation team and an extensive evaluation are necessary steps before listing for transplantation. Immunosuppression is part of life-long therapy after transplantation, and children continue to have high medical needs. Serious complications include acute cellular rejection, graft-versus-host disease, infection, and post-transplant lymphoproliferative disease. However, intestinal transplantation has led to improved outcomes in recent years and is a viable life-saving option for many children with intestinal failure.

Chronic Mucosal Inflammation in Pediatric Intestinal Failure Patients-A Unique Phenomenon.

INTRODUCTION/OBJECTIVES: As intestinal failure (IF) management improves and long-term survival rate increases, its physiological complications have become more apparent. The development of chronic intestinal inflammation resembling inflammatory bowel disease (IBD) in this population has been reported, but the literature describing it in detail is sparse. The present study was designed to characterize children with IF who developed chronic intestinal inflammation and identify the potential predisposing clinical factors. METHODS: This retrospective study was based on the electronic medical records of pediatric patients seen at the Cincinnati Children's Hospital Medical Center between January 2000 and July 2022. Demographic and medical history data were collected and compared between children with IF that developed chronic intestinal inflammation and children with IF that did not develop chronic intestinal inflammation. RESULTS: During the follow-up period, 23 children were diagnosed with chronic intestinal inflammation. Of these, 12 (52%) were males, with a median age of 4.5 (3-7) years at diagnosis. Nearly one-third of the patients had gastroschisis (31%), followed by necrotizing enterocolitis (26%), and malrotation and volvulus (21.7%). More children in the chronic intestinal inflammation group lacked an ileocecal valve (ICV) and adjoining distal ileum as compared to the short bowel syndrome (SBS)-IF control group (15 patients, 65% vs 8 patients, 33%). Moreover, more children in the chronic intestinal inflammation group had undergone a prior lengthening procedure than the SBS-IF control group (5 patients, 21.7% vs. 0, respectively). DISCUSSION: SBS patients are at risk of relatively early onset chronic intestinal inflammation. The absence of an ICV (and adjoin ileum) and prior lengthening procedures emerge as factors associated with the risk of IBD in these patients.

Pitfalls of iron supplementation in parenteral nutrition admixtures for children with intestinal failure.

BACKGROUND: Pediatric patients with intestinal failure are at increased risk for iron deficiency. Supplementation is not routinely included in parenteral nutrition solutions. There is currently limited research related to the safety of iron supplementation in parenteral nutrition and for intravenous forms used in patients with intestinal failure. Current American Society for Parenteral and Enteral Nutrition and ESPGHAN guidelines promote the use of enteral iron, acknowledging the risks of using iron supplementation within parenteral nutrition admixtures. METHODS: We review a patient case and the current available literature related to iron in parenteral nutrition. RESULTS: Five major concerns are identified: peroxidation reactions, incompatibility, hypersensitivity, infection risk, and iron overload. CONCLUSION: We propose an argument against the preferential use of iron supplementation within parenteral nutrition in children with intestinal failure when enteral supplementation or intermittent parenteral infusion may be sufficient.

Operational tolerance after pediatric composite liver-pancreas-intestine transplantation following severe graft-versus-host disease.

BACKGROUND: While operational tolerance has been previously described in isolated intestinal transplant, reports of this phenomenon in combined liver-intestine transplant are lacking. CASE DESCRIPTION: We detail a unique case of a patient who received a composite allograft including liver, pancreas, and small bowel due to short gut syndrome secondary to gastroschisis complicated by volvulus. The indication for transplantation was permanent dependence on total parenteral nutrition, end-stage liver disease, recurrent sepsis, and persistent stomal variceal hemorrhage. The patient developed severe graft-versus-host disease with grade 3 skin involvement, ophthalmic, and pulmonary involvement with 53% donor T-cell chimerism. She required aggressive therapy including high-dose methylprednisolone, rituximab, cyclophosphamide, and alemtuzumab. Due to infection concerns following depletion of her lymphocytes, immunosuppression was discontinued with close surveillance of her allograft. Nearly 10 years later, the patient has continued off all immunosuppression without evidence of rejection or graft dysfunction and demonstrates immunocompetence with normal functional immune assays and development of appropriate live vaccination titers. CONCLUSION: This report of operational tolerance following pediatric composite liver-pancreas-intestine transplantation provides evidence that the complex immunologic balance in intestinal transplantation may on rare occasions favor immunosuppression reduction or even discontinuation. Future trials of immunosuppression minimization in this population may be warranted.

Safety Findings in Pediatric Patients During Long-Term Treatment With Teduglutide for Short-Bowel Syndrome-Associated Intestinal Failure: Pooled Analysis of 4 Clinical Studies.

BACKGROUND: This analysis assessed combined safety data from 4 clinical studies of teduglutide in pediatric patients with short-bowel syndrome-associated intestinal failure (SBS-IF). METHODS: Safety data from teduglutide-treated patients in 4 clinical trials were pooled. The completed 12-week and 24-week phase 3 core studies (NCT01952080/EudraCT 2013-004588-30 and NCT02682381/EudraCT 2015-002252-27) enrolled children aged 1-17 years with SBS-IF. Patients could elect to enroll in ongoing open-label extensions (NCT02949362/EudraCT 2016-000863-17 and NCT02954458/EudraCT 2016-000849-30). Interim data from ongoing studies were included. RESULTS: Safety data are reported for 89 pediatric patients treated with teduglutide for a median (range) of 51.7 (5.0-94.7) weeks. Adverse events (AEs) were reported in all patients; the most common were vomiting (51.7%), pyrexia (43.8%), upper respiratory tract infection (41.6%), and cough (33.7%). Thirty-five patients (39.3%) had AEs considered related to teduglutide treatment; abdominal pain and vomiting were most frequent (5.6% each). Three serious AEs in 3 patients (3.4%) were considered related to teduglutide treatment: ileus, d-lactic acidosis, and gastrointestinal obstruction due to hard stools. All 3 events resolved. One cecal polyp was detected, which was not biopsied or found on repeat colonoscopy. No cases of neoplasia occurred. CONCLUSION: Based on integrated data from 4 clinical studies, including long-term follow-up for ≤161 weeks, teduglutide had a safety profile consistent with the individual core pediatric studies and as expected for pediatric patients with SBS-IF who never received teduglutide. The most frequent AEs reflected treatment with teduglutide, complications of the underlying disease, and typical childhood illnesses.

Safety and Efficacy of Teduglutide in Pediatric Patients With Intestinal Failure due to Short Bowel Syndrome: A 24-Week, Phase III Study.

BACKGROUND: This study evaluated the safety and efficacy of teduglutide in pediatric patients with short bowel syndrome-associated intestinal failure (SBS-IF). METHODS: A 24-week, phase III trial with 2 randomized, double-blind teduglutide dose groups and a nonblinded standard of care (SOC) arm was used; patients received 0.025 mg/kg or 0.05 mg/kg teduglutide once daily. Safety end points included treatment-emergent adverse events (TEAEs) and growth parameters. The primary efficacy/pharmacodynamic end point was the number of patients who achieved a ≥20% reduction in parenteral support (PS) from baseline at week 24. RESULTS: All 59 enrolled patients completed the study (0.025 mg/kg, n = 24; 0.05 mg/kg, n = 26; SOC, n = 9). Baseline demographics and disease characteristics were comparable among groups. TEAEs were reported by 98% and 100% of patients in the teduglutide and SOC groups, respectively. The most common TEAEs in the teduglutide-treated groups were pyrexia and vomiting. The primary end point was achieved by 13 (54.2%), 18 (69.2%), and 1 (11.1%) patients who received 0.025 mg/kg teduglutide, 0.05 mg/kg teduglutide, and SOC, respectively (P < 0.05 vs SOC). Both 0.025-mg/kg and 0.05-mg/kg teduglutide groups showed clinically significant reductions in PS volume (P < 0.05 vs SOC), PS calories, days per week and hours per day of PS infusions, and increases in enteral nutrition and plasma citrulline at week 24 compared with baseline. Two (8.3%, 0.025 mg/kg teduglutide) and 3 patients (11.5%, 0.05 mg/kg teduglutide) achieved enteral autonomy. CONCLUSION: The safety profile of teduglutide was similar to that reported previously in children and adults. Treatment with teduglutide was associated with significant reductions in PS for pediatric patients with SBS-IF over 24 weeks.

Evaluation of a change in cytomegalovirus prevention strategy following pediatric solid organ transplantation.

BACKGROUND: An optimal cytomegalovirus (CMV) prevention strategy following solid organ transplantation (SOT) remains uncertain. This study reports on the rates of CMV events following a change in a local prevention guideline involving increased surveillance, earlier transition to oral valganciclovir, and decreased CMV-immunoglobulin use. METHODS: A retrospective cohort study utilizing historical controls evaluated the rates of CMV invasive disease pre- and post-intervention among pediatric heart, liver, and kidney recipients. Outcomes were recorded for the 4 years pre- and post-intervention, 9/2009-10/2017. Logistic regression was used to estimate the risk of a CMV event. RESULTS: There was no difference in the rates of CMV invasive disease between the two study groups (P = 1). An increase in the detection of CMV events occurred (P = .04), predominantly asymptomatic CMV infection. This increase was independently associated with increased surveillance testing among high-risk heart and liver recipients, aOR 1.08 (1.06-1.12). Surprisingly, 28.9% of CMV events occurred during antiviral prophylaxis. CONCLUSIONS: Modification of the local CMV prevention guideline did not result in an increase in CMV invasive disease. CMV events occurred while on prophylaxis, highlighting a potential difference from adult solid organ transplant (SOT) and emphasizing the potential need for monitoring on prophylaxis in the pediatric population.

Evidence-Based Strategies and Recommendations for Preservation of Central Venous Access in Children.

Children with chronic illness often require prolonged or repeated venous access. They remain at high risk for venous catheter-related complications (high-risk patients), which largely derive from elective decisions during catheter insertion and continuing care. These complications result in progressive loss of the venous capital (patent and compliant venous pathways) necessary for delivery of life-preserving therapies. A nonstandardized, episodic, isolated approach to venous care in these high-need, high-cost patients is too often the norm, imposing a disproportionate burden on affected persons and escalating costs. This state-of-the-art review identifies known failure points in the current systems of venous care, details the elements of an individualized plan of care, and emphasizes a patient-centered, multidisciplinary, collaborative, and evidence-based approach to care in these vulnerable populations. These guidelines are intended to enable every practitioner in every practice to deliver better care and better outcomes to these patients through awareness of critical issues, anticipatory attention to meaningful components of care, and appropriate consultation or referral when necessary.

Esophageal dysmotility: An intrinsic feature of megacystis, microcolon, hypoperistalsis syndrome (MMIHS).

OBJECTIVES: Megacystis-microcolon-hypoperistalsis syndrome (MMIHS) also called Berdon's Syndrome, is a smooth muscle myopathy that results in an enlarged bladder, microcolon, and small bowel hypoperistalsis. In our series of six patients with this disorder, all had disordered swallowing. Therefore, we prospectively characterized esophageal structure and function in all. METHODS: Diagnoses had been established by contrast radiography, small bowel manometry, and urodynamic studies. To investigate the esophagus, we endoscoped and biopsied the esophagus of each patient on multiple occasions. All patients also underwent water soluble contrast esophagography and esophageal manometry. RESULTS: Upon careful questioning, all patients had swallowing dysfunction, and the majority of their enteral intake was via gastrostomy or gastrojejunostomy. All took some oral alimentation, but eating was slow and none could aliment themselves completely by the oral route, receiving 50% or less of their calories by mouth. Four had megaesophagus whereas the esophagus of the two youngest was of normal caliber. All had eosinophilic esophagitis and/or esophageal Candidiasis from time to time, but successful treatment of these findings failed to improve their symptoms. Manometry revealed normal lower esophageal sphincter (LES) resting tone and normal LES relaxation, but for all, peristalsis was absent in the esophageal body. CONCLUSIONS: This series expands the spectrum of findings in MMIHS, to include a primary motility disorder of the esophageal body. As patients age, the esophageal caliber appears to increase. Successful treatment of neither esophageal eosinophilia nor Candidiasis is effective in ameliorating the motility disorder. If our findings are confirmed in more patients with MMIHS, this disorder should be renamed, megacystis-microcolon-intestinal-and esophageal hypoperistalsis syndrome. TYPE OF STUDY: Prognosis study, Level IV (case series).

Serum Unconjugated Bile Acids and Small Bowel Bacterial Overgrowth in Pediatric Intestinal Failure: A Pilot Study.

BACKGROUND: We determined qualitative and quantitative serum unconjugated bile acid (SUBA) levels among children with history of intestinal failure (IF) and suspected small bowel bacterial overgrowth (SBBO). METHODS: This was a single-center, case-control pilot study conducted at Cincinnati Children's Hospital Medical Center. Children with history of IF and suspected SBBO were enrolled as subjects. Age-matched children without IF or suspected SBBO served as controls. All participants underwent small bowel fluid sampling for microbial culture analysis. Additionally, serum fractionated and total bile acids were measured by liquid chromatography-mass spectrometry at enrollment and following treatment for SBBO. RESULTS: SUBA concentrations were elevated in IF subjects (median 1.16 µM, range 0.43-10.65 µM) compared with controls (median 0.10 µM, range 0.05-0.18 µM, P = 0.001). Among SUBA, chenodeoxycholic acid (CDCA) was significantly elevated in subjects (median 0.8 µM, range 0-7.08 µM) compared with controls (median 0 µM, range 0-0.03 µM, P = 0.012). When controls were excluded from analysis, IF subjects with positive aspirates for SBBO demonstrated higher concentration of CDCA (median 7.36 µM, range 1.1-8.28 µM) compared with IF subjects with negative aspirates (median 0.18 µM, range 0-1.06 µM, P = 0.017). Treatment for SBBO did not alter SUBA concentration. CONCLUSIONS: SUBA concentrations are elevated in children with history of IF and presumed SBBO compared with non-IF controls. CDCA was more prevalent in IF subjects with positive aspirates for SBBO compared with IF subjects with negative aspirates. The determination of SUBA concentration may be a useful surrogate to small bowel fluid aspiration in the diagnosis of SBBO in children with history of IF.