Jeffrey A. Rudolph

Natural History of Pediatric Intestinal Failure: Initial Report from the Pediatric Intestinal Failure Consortium

OBJECTIVE To characterize the natural history of intestinal failure (IF) among 14 pediatric centers during the intestinal transplantation era. STUDY DESIGN The Pediatric Intestinal Failure Consortium performed a retrospective analysis of clinical and outcome data for a multicenter cohort of infants with IF. Entry criteria included infants <12 months receiving parenteral nutrition (PN) for >60 continuous days. Enteral autonomy was defined as discontinuation of PN for >3 consecutive months. Values are presented as median (25th, 75th percentiles) or as number (%). RESULTS 272 infants with a gestational age of 34 weeks (30, 36) and birth weight of 2.1 kg (1.2, 2.7) were followed for 25.7 months (11.2, 40.9). Residual small bowel length in 144 patients was 41 cm (25.0, 65.5). Diagnoses were necrotizing enterocolitis (71, 26%), gastroschisis (44, 16%), atresia (27, 10%), volvulus (24, 9%), combinations of these diagnoses (46, 17%), aganglionosis (11, 4%), and other single or multiple diagnoses (48, 18%). Prescribed medications included oral antibiotics (207, 76%), H2 blockers (187, 69%), and proton pump inhibitors (156, 57%). Enteral feeding approaches varied among centers; 19% of the cohort received human milk. The cohort experienced 8.9 new catheter-related blood stream infections per 1000 catheter days. The cumulative incidences for enteral autonomy, death, and intestinal transplantation were 47%, 27%, and 26%, respectively. Enteral autonomy continued into the fifth year after study entry. CONCLUSIONS Children with IF endure significant mortality and morbidity. Enteral autonomy may require years to achieve. Improved medical, nutritional, and surgical management may reduce time on PN, mortality, and need for transplantation.

Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter Cohort Study

OBJECTIVES In a large cohort of children with intestinal failure (IF), we sought to determine the cumulative incidence of achieving enteral autonomy and identify patient and institutional characteristics associated with enteral autonomy. STUDY DESIGN A multicenter, retrospective cohort analysis from the Pediatric Intestinal Failure Consortium was performed. IF was defined as severe congenital or acquired gastrointestinal diseases during infancy with dependence on parenteral nutrition (PN) >60 days. Enteral autonomy was defined as PN discontinuation >3 months. RESULTS A total of 272 infants were followed for a median (IQR) of 33.5 (16.2-51.5) months. Enteral autonomy was achieved in 118 (43%); 36 (13%) remained PN dependent and 118 (43%) patients died or underwent transplantation. Multivariable analysis identified necrotizing enterocolitis (NEC; OR 2.42, 95% CI 1.33-4.47), care at an IF site without an associated intestinal transplantation program (OR 2.73, 95% CI 1.56-4.78), and an intact ileocecal valve (OR 2.80, 95% CI 1.63-4.83) as independent risk factors for enteral autonomy. A second model (n = 144) that included only patients with intraoperatively measured residual small bowel length found NEC (OR 3.44, 95% CI 1.36-8.71), care at a nonintestinal transplantation center (OR 6.56, 95% CI 2.53-16.98), and residual small bowel length (OR 1.04 cm, 95% CI 1.02-1.06 cm) to be independently associated with enteral autonomy. CONCLUSIONS A substantial proportion of infants with IF can achieve enteral autonomy. Underlying NEC, preserved ileocecal valve, and longer bowel length are associated with achieving enteral autonomy. It is likely that variations in institutional practices and referral patterns also affect outcomes in children with IF.

NOD2 gene polymorphism rs2066844 associates with need for combined liver-intestine transplantation in children with short-gut syndrome.

OBJECTIVES:The nucleotide-binding oligomerization protein 2 (NOD2) gene single nucleotide polymorphisms (SNPs) associated with Crohns disease were recently associated with severe rejection after small-bowel transplantation (SBTx). The purpose of this study was to re-test this association and explore whether deficient innate immunity suggested by the NOD2 SNPs predisposes to intestine failure requiring isolated SBTx or combined liver–intestine failure requiring combined liver–SBTx (LSBTx).METHODS:Archived DNA from 85 children with primary isolated SBTx or LSBTx was genotyped with Taqman biallelic discrimination assays. To minimize confounding effects of racial differences in minor allele frequencies (MAFs), allelic associations were tested in 60 Caucasian recipients (discovery cohort). Replication was sought in an independent cohort of 39 Caucasian pediatric and adult SBTx patients.RESULTS:MAF for rs2066845 and rs2066847 was similar to that seen in 538 healthy North American Caucasians. In the discovery cohort, MAF for rs2066844 was significantly higher in LSBTx (13.5 vs. 3.6%, P=0.0007, Fishers exact test), but not in isolated SBTx recipients (2.2 vs. 3.6%, P=NS), when compared with 538 healthy Caucasians. In addition, among LSBTx recipients who received identical immunosuppression, the minor allele of rs2066844 associated with early rejection in linear regression analysis (P=0.028) (all but one of the risk alleles were found in rejectors), decreased survival (P=0.015, log-rank, Kaplan–Meier analysis), and a 20-fold greater hazard of septic death in proportional hazard analysis (P=0.030). Steroid-resistant (severe) rejection and graft loss were associated with isolated SBTx (P=0.036 and 0.082, respectively), but not with NOD2 SNPs. The association between rs2066844 and combined liver–intestine failure requiring LSBTx was significant in the replication cohort (P=0.014), and achieved greater significance in the combined cohort (P=0.00006).CONCLUSIONS:The NOD2 SNP rs2066844 associates with combined liver and intestinal failure in subjects with short-gut syndrome, who require combined liver–intestine transplantation, and secondarily with early rejection and septic deaths.

Current concepts in the medical management of pediatric intestinal failure.

Purpose of reviewMedical management of children with intestinal failure has gained increased relevance in recent years, in part owing to the growth of small bowel transplantation as a therapeutic option. The capacity of a patient to attain enteral autonomy through intestinal adaptation is critical in the decision process of whether or not transplantation is beneficial. This article reviews several important advances in the field of intestinal rehabilitation, focusing on enhancing adaptation and briefly mentioning recent insights into the morbidity of intestinal failure. Recent findingsThe field of intestinal rehabilitation has developed into a multidisciplinary venture with many facets. From a medical standpoint, intestinal adaptation efforts have come to focus upon identifying objective prognostic factors and therapies geared to increase functional gut mass. However, the stalwart of adaptive therapy remains the provision of enteral feeds, which must be balanced with nutritional goals. Although the common complications of parenteral nutrition therapy continue to affect outcomes, new therapies offer promise with regard to prevention of morbidity in this population. SummaryMedical intestinal rehabilitative therapy has progressed from the solitary concept of providing sufficient calories for growth to the promotion of enteral autonomy via intestinal adaptation. As strategies evolve with enhancing adaptation and minimizing morbidity, a clearer perspective will be gained regarding the difficult choice of rehabilitation versus transplantation as optimal therapy.

New causes and treatments for infectious diarrhea in children.

Infectious diarrhea is a universal and important health problem in the pediatric population. An expanding number of potential viral, bacterial, and parasitic pathogens have been associated with diarrheal disease. However, the epidemiologic association of a microorganism with diarrhea is only one step in the process of identifying new pathogens. Once the virulence mechanisms of these organisms are elucidated, a causal relationship can be more readily defined. This article reviews the etiologic agents of diarrhea in the pediatric population and focuses on the newer treatment and prevention modalities, including probiotics and vaccinations, which are used increasingly to combat these diseases.

Race affects outcome among infants with intestinal failure.

Objective: Intestinal failure (IF) is a rare, devastating condition associated with significant morbidity and mortality. We sought to determine whether ethnic and racial differences were associated with patient survival and likelihood of receiving an intestinal transplant in a contemporary cohort of children with IF. Methods: This was an analysis of a multicenter cohort study with data collected from chart review conducted by the Pediatric Intestinal Failure Consortium. Entry criteria included infants ⩽12 months receiving parenteral nutrition (PN) for ≥60 continuous days and studied for at least 2 years. Outcomes included death and intestinal transplantation (ITx). Race and ethnicity were recorded as they were in the medical record. For purposes of statistical comparisons and regression modeling, categories of race were consolidated into “white” and “nonwhite” children. Results: Of 272 subjects enrolled, 204 white and 46 nonwhite children were available for analysis. The 48-month cumulative incidence probability of death without ITx was 0.40 for nonwhite and 0.16 for white children (P < 0.001); the cumulative incidence probability of ITx was 0.07 for nonwhite versus 0.31 for white children (P = 0.003). The associations between race and outcomes remained after accounting for low birth weight, diagnosis, and being seen at a transplant center. Conclusions: Race is associated with death and receiving an ITx in a large cohort of children with IF. This study highlights the need to investigate reasons for this apparent racial disparity in outcome among children with IF.

sTREM-1 and LBP in central venous catheter-associated bloodstream infections in pediatric intestinal failure.

Objective: Central venous catheter–associated bloodstream infections (CVC-BSIs) are a major cause of morbidity and mortality in the pediatric intestinal failure (IF) population. We assessed plasma lipopolysaccharide-binding protein (LBP) and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as biomarkers for CVC-BSI. We hypothesized that sTREM-1 and LBP rise with BSI and decline following treatment, and that baseline LBP is higher in the IF population than in controls. Patients and Methods: Patients younger than 4 years were recruited from the IF registry at Cincinnati Childrens Hospital. LBP and sTREM-1 levels were measured on 22 patients with IF at baseline, 17 patients with IF with BSIs, and 11 healthy controls. Results: Mean sTREM-1 level (pg/mL) and LBP level (&mgr;g/mL) rose with CVC-BSI over baseline (115.0 ± 51.2 vs 85.9 ± 27.6, P = 0.011 and 79.8 ± 45.4 vs 20.5 ± 11.3, P < 0.001, respectively) and declined following antibiotic therapy (115.0 ± 51.2 vs 77.9 ± 29.8, P = 0.003 and 79.8 ± 45.4 vs 26.2 ± 10.8, P < 0.001, respectively). Receiver operating characteristic curves showed that neither sTREM-1 nor LBP is sufficient to predict bacteremia versus fever without bacteremia (area under these curves = 0.57 and 0.82, respectively). Baseline LBP was higher in hospitalized patients than in outpatients (27.5 ± 8.7 vs 13.5 ± 9.2, P = 0.002), patients with previous BSIs versus those without (23.5 ± 10.4 vs 10.1 ± 8.3, P = 0.016), and those listed for transplantation versus those not listed (29.6 ± 9.8 vs 16.2 ± 9.5, P = 0.033). Conclusions: sTREM-1 and LBP rise with CVC-BSI in IF and decline after treatment; however, neither distinguishes infection from nonbacteremic febrile episodes. Baseline LBP may be a marker of disease severity in IF.

Anatomic and histologic variability of epithelial apoptosis in small bowel transplants

Pasternak BA, Collins MH, Tiao GM, Rudolph JA, Alonso MH, Ryckman FC, Kocoshis SA. Anatomic and histologic variability of epithelial apoptosis in small bowel transplants.
Pediatr Transplantation 2010: 14: 71–76.

Mucosal plasma cell barrier disruption during intestine transplant rejection.

Background Intestinal allograft mucosa undergoes repopulation with host immunocytes. However, critical changes within key immunocyte subsets are not known. Methods To explain acute cellular rejection after intestine transplantation (ITx) on the basis of altered mucosal immunocytes, rejecting and rejection-free ITx allografts (n=17) were compared with genome-wide expression arrays. Cells identified by cell/lineage-specific genes were evaluated by immunohistochemistry. The corresponding phenotype and donor-specific alloreactivity were characterized in peripheral blood. Time-dependent changes in candidate cell(s) were evaluated in biopsies from an independent cohort of 12 children with ITx. Results Among 107 differentially expressed genes, three B-cell lineage–specific genes, CCR10, STAP1, and IGLL1, were down-regulated during ITx rejection and were selected for and achieved technical quantitative reverse transcription polymerase chain reaction replication. Down-regulation of the immunoglobulin (Ig)A+ plasma cell–specific CCR10 gene correlated with decreased mature mucosal CD138+ plasma cell numbers in corresponding biopsy specimens (r=0.761, P=0.006) and inversely correlated with enhanced alloreactivity of CD154+ T-cytotoxic memory cells (r=−0.56, P=0.031), which predict acute cellular rejection with high sensitivity. An independent cohort of serial biopsy specimens from 12 ITx recipients (1) confirmed relative CD138+ plasma cell depletion during rejection (P=0.042) and (2) showed increased IgG+-to-IgA+ cell ratios within 4 hr of reperfusion in rejection-prone allografts (P=0.037) and during ITx rejection (P=0.025), compared with rejection-free allografts. No differences existed late after ITx. Increased peripheral IgG+ CD27+ CD19+ memory B cells (P=0.004) were seen during ITx rejection in archived peripheral blood lymphocyte from test and replication cohorts. Conclusions Protracted depletion of the mucosal CD138+ plasma cell barrier and early mucosal infiltration with memory IgG+ cells characterize the rejection-prone intestine allograft. Mucosal IgA+ plasma cell barrier reconstitution may augur resolution of ITx rejection.

Bloodstream Infections in Patients With Intestinal Failure Presenting to a Pediatric Emergency Department With Fever and a Central Line.

Objective Previous small studies have found a high occurrence of bloodstream infections (BSIs) in patients with intestinal failure, and these rates are higher than reported rates in other pediatric populations with central lines. The primary study objective was to describe the occurrence of BSIs in patients with intestinal failure who present to the pediatric emergency department (ED) with fever. Methods This 5-year retrospective chart review included febrile patients with intestinal failure and central lines who presented to the Childrens Hospital of Pittsburgh ED between 2006 and 2011. Each febrile episode was analyzed at the visit level. Results During the study, 72 patients with 519 febrile episodes were identified. Central blood cultures were obtained in 93% (480/519) of episodes and 69% (330/480) were positive. Of all BSIs, 38% (124/330) were polymicrobial, 32% (105/330) were a single gram-positive organism, 25% (84/330) were a single gram-negative organism, and 5% (17/330) were a single fungal organism. Of the bacterial pathogens, 48% (223/460) were gram-negative. Overall, 60% were enteric organisms. Conclusions Pediatric patients with intestinal failure and central lines have a high occurrence of BSIs with 69% of cultures positive in this study of ED febrile episodes. In contrast to reports in other populations with central lines, BSI occurrence in patients with intestinal failure and fever is higher and larger proportions are gram-negative and enteric organisms. For these patients, we recommend central and peripheral blood cultures, empiric broad spectrum antibiotics targeting gram-negative and enteric organisms, and hospital admission.