Samuel A. Kocoshis

A new syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction

In the past decade, we have studied four unrelated children with what we believe is a previously unreported disorder affecting the bone marrow and exocrine pancreas. During infancy these patients had the onset of severe, transfusion-dependent, macrocytic anemia plus a variable degree of neutropenia and thrombocytopenia. Their bone marrows had normal cellularity but were characterized by remarkable vacuolization of erythroid and myeloid precursors, hemosiderosis, and ringed sideroblasts. The vacuoles probably represented manifestations of cellular degeneration and death. In two patients, in vitro bone marrow cultures showed abnormal erythroid and myeloid progenitor cell growth and, in one child, abnormal vacuolated erythroid colonies. Family histories were unrevealing, parents were hematologically normal, and both sexes were involved. There was no evidence of specific nutritional deficiencies or exposure to agents associated with marrow vacuolization. A number of therapeutic interventions produced no effect. One child had clinical malabsorption. This child and one other had extensive pancreatic fibrosis at autopsy. The other two patients had findings indicating exocrine pancreatic dysfunction. Two children had splenic atrophy. This new syndrome, with associated bone marrow and exocrine pancreatic dysfunctions, differs in several respects from the syndrome of pancreatic liposis and neutropenia described by Shwachman et all and Bodian et al, and from other conditions with vacuolization of the marrow or sideroblastosis.

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.

Medical management of pediatric intestinal failure

The outcome for children with congenital enteropathies or massive surgical resections has improved significantly over the past two decades. Advances in understanding of the pathophysiology of intractable diarrhea and of the mutations causing many of the congenital enteropathies have enabled initiation of preventive measures for intractable diarrhea, and have enabled clinicians to provide focused treatment of immune-mediated congenital diarrheal illnesses. Children with surgical short bowel syndrome also face an improved outcome because of improvements in the composition of parenteral nutrition (TPN) and in enteral alimentation strategies. It is now recognized that, through adaptation, small intestinal surface area and absorptive function may improve over time to facilitate emancipation from parenteral nutrition. Beyond provision of enteral nutrition, ancillary therapies such as judicious use of acid suppression, antibiotics, prokinetic agents, and soluble fiber seem to accelerate the rate of adaptation in young children. In the future, trophic hormones such as epidermal growth factor (EGF) or glucagon-like peptide 2 (GLP-2) may become routine members of the therapeutic armamentarium for surgical short bowel syndrome, thus further improving outcomes.

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.

Use of Cromolyn in Combined Gastrointestinal Allergy

A double-blind clinical trial was undertaken to evaluate the efficacy of orally given cromolyn sodium vs that of pacebo in the management of food allergy. Fourteen children, aged 2 to 15 years, with milk allergy and concomitant allergies to one or more foods were given cromolyn or placebo. Eleven had positive intradermal skin reactions or coproantibodies to offending antigens. Treatment was begun while the children were receiving elimination diets; they were challenged with specific antigen only after 48 hours of drug administration. Crossover took place if the initial agent was ineffective. Cromolyn afforded protection in 11 of 13 trials, whereas placebo was effective in only three of nine trials. By chi 2 analysis, the drugs effect was statistically significant.

Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of Teduglutide in Pediatric Short Bowel Syndrome

Objective To determine safety and pharmacodynamics/efficacy of teduglutide in children with intestinal failure associated with short bowel syndrome (SBS‐IF). Study design This 12‐week, open‐label study enrolled patients aged 1‐17 years with SBS‐IF who required parenteral nutrition (PN) and showed minimal or no advance in enteral nutrition (EN) feeds. Patients enrolled sequentially into 3 teduglutide cohorts (0.0125 mg/kg/d [n = 8], 0.025 mg/kg/d [n = 14], 0.05 mg/kg/d [n = 15]) or received standard of care (SOC, n = 5). Descriptive summary statistics were used. Results All patients experienced ≥1 treatment‐emergent adverse event; most were mild or moderate. No serious teduglutide‐related treatment‐emergent adverse events occurred. Between baseline and week 12, prescribed PN volume and calories (kcal/kg/d) changed by a median of −41% and −45%, respectively, with 0.025 mg/kg/d teduglutide and by −25% and −52% with 0.05 mg/kg/d teduglutide. In contrast, PN volume and calories changed by 0% and −6%, respectively, with 0.0125 mg/kg/d teduglutide and by 0% and −1% with SOC. Per patient diary data, EN volume increased by a median of 22%, 32%, and 40% in the 0.0125, 0.025, and 0.05 mg/kg/d cohorts, respectively, and by 11% with SOC. Four patients achieved independence from PN, 3 in the 0.05 mg/kg/d cohort and 1 in the 0.025 mg/kg/d cohort. Study limitations included its short‐term, open‐label design, and small sample size. Conclusions Teduglutide was well tolerated in pediatric patients with SBS‐IF. Teduglutide 0.025 or 0.05 mg/kg/d was associated with trends toward reductions in PN requirements and advancements in EN feeding in children with SBS‐IF. Trial registration ClinicalTrials.gov: NCT01952080; EudraCT: 2013‐004588‐30.

Brewer's yeast and Saccharomyces boulardii both attenuate Clostridium difficile-induced colonic secretion in the rat

Saccharomyces boulardii (Sb), a nonpathogenicyeast, has been used to prevent recurrences ofClostridium difficile (C.diff)-associated diarrhea. Asingle report suggested that treatment withSaccharomyces cerevisiae (Sc), commonly called brewers yeast(BY), facilitates treatment of persistent C.diffinfection. We conducted this experiment to determinewhether C.diff toxin A-induced colonic secretion in the rat is blunted by pretreatment with eitherSb or BY. We employed closed cecal pouches in two groupsof five adult male Sprague-Dawley rats fed with standardchow for five days prior to the experiment, another group whose water was supplemented with20 × 109 colony-forming units (CFU) ofSb per day for five days, and another group whose waterwas supplemented with 20 × 109 CFU ofSc per day for five days. Cecal pouches were infused for 3 hr with one ofthe following: (1) normal saline alone for a controlgroup, or (2) normal saline plus 5 μg of C.diff toxinA (for the other control group and for the two experimental groups). Water movement wasmeasured by a nonabsorbable marker technique. Sodiummovement and permeability to mannitol were alsomeasured. Prior to the infusion, cecal contents werequantitatively cultured. In the three animals whose ceca werecolonized with less than 106 CFU of eitheryeast per gram wet cecal content, toxin A-inducedsecretion could not be attenuated. In contrast, animalswhose ceca were colonized with more than106 CFU of either yeast per gram of wet cecalcontent showed significantly less secretion after toxinA application than those which were not fed yeast. S.cerevisiae reduced secretion by half (N = 5, P = 0.039 forwater, 0.044 for sodium) and Sb by 75% (N = 4, P = 0.015for water, 0.034 for sodium). Toxin-induced increases inpermeability to [3H]mannitol from systemic circulation to cecum could not be blunted byeither yeast. We conclude that rat ceca can be colonizedby either organism and that both organisms reduce C.difftoxin A-mediated secretion. We speculate that both organisms might have benefit in humanC.diff-associated enterocolitis. Further studies oftheir mechanisms of action as well as clinical trialsfor the prevention and treatment of human C.diffinfections should be pursued.

Vitamin D deficiency and low bone mineral density in pediatric and young adult intestinal failure.

Objectives: The aim of the present study was to determine the prevalence and predisposing factors for vitamin D deficiency and low bone mineral density (BMD) in patients with intestinal failure (IF). Methods: A retrospective review of patients with IF managed at the Cincinnati Childrens Hospital Medical Center. IF was defined as history of parenteral nutrition (PN) >30 days. Vitamin D deficiency was defined as serum 25-hydroxyvitamin D (25 (OH) D) <20 ng/dL. Reduced BMD was defined using dual x-ray absorptiometry z score ⩽–2. A binary logistic regression model was used to test for association of significant risk factors and the outcome variables after univariate analyses. Results: One hundred and twenty-three patients with median age of 4 years (range 3–22 years) were evaluated. Forty-nine (39.8%) patients had at least a documented serum 25 (OH) D deficiency during the study interval, whereas 10 of 80 patients (12.5%) with dual x-ray absorptiometry scans completed had a low BMD z score. Age at study entry was associated with both 25 (OH) D deficiency (P = 0.01) and low BMD z score (P = 0.03). Exclusive PN at study entry was associated with reduced bone mass (P = 0.03). There was no significant association between vitamin D deficiency and low BMD z score (P = 0.31). Conclusions: The risk of 25 (OH) D deficiency and low BMD z score increases with age among patients with IF. Strategies for monitoring and preventing abnormal bone health in older children receiving exclusive PN need to be developed and evaluated.

Multiple micronutrient deficiencies among patients with intestinal failure during and after transition to enteral nutrition.

OBJECTIVES To determine the prevalence of deficiencies of specific micronutrients (iron, zinc, magnesium, phosphorus, selenium, copper, folate, and vitamins A, D, E, and B12) in children with intestinal failure (IF), and to identify risk factors associated with developing these deficiencies. STUDY DESIGN This study was a retrospective review of prospectively collected data from 178 children with IF managed by the Intestinal Care Center of Cincinnati Childrens Hospital Medical Center between August 1, 2007, and July 31, 2012. Transition to full enteral nutrition (FEN) was defined as the period during which the patient received between 20% and 100% of estimated required nutrition enterally. FEN was defined as the patients ability to tolerate 100% estimated required nutrition enterally for >2 weeks. RESULTS Necrotizing enterocolitis was the most common cause of IF (27.5%). Iron was the most common micronutrient deficiency identified both during (83.9%) and after (61%) successful transition to FEN, with a significant reduction in the percentage of patients with iron deficiency between these 2 periods (P = .003). Predictors of micronutrient deficiency after successful transition to FEN included birth weight (P = .03), weight percentile (P = .02), height percentile (P = .04), and duration of parenteral nutrition (PN) (P = .013). After multivariate adjustments, only duration of PN remained statistically significant (P = .03). CONCLUSION Micronutrient deficiencies persist in patients with IF during and after transition to FEN. These data support the need for routine monitoring and supplementation of these patients, especially those on prolonged PN.

Nutrition management of infants with surgical short bowel syndrome and intestinal failure.

Appropriate nutrition recommendations are important for the successful management of the infant with an injured gastrointestinal tract postsurgery who is at risk for intestinal failure. Management strategies that can be used to augment successful adaptation and prevent liver disease are summarized in this review. These include appropriate postoperative fluid and electrolyte management, modification of parenteral nutrition to minimize intestinal failure-associated liver disease, early and aggressive enteral feeding advancement, the use of hormonal and trophic agents, prevention of central line-associated bloodstream infections using ethanol lock, appropriate treatment, and prevention of pathologic small bowel bacterial overgrowth.