Conrad R. Cole

The rate of bloodstream infection is high in infants with short bowel syndrome: Relationship with small bowel bacterial overgrowth, enteral feeding and inflammatory and immune responses

OBJECTIVE This pilot study in parenteral nutrition-dependent infants with short bowel syndrome (SBS) evaluated the impact of feeding route and intestinal permeability on bloodstream infection (BSI), small bowel bacterial overgrowth (SBBO), and systemic immune responses, as well as fecal calprotectin as a biomarker for SBBO. STUDY DESIGN Ten infants (ages 4.2-15.4 months) with SBS caused by necrotizing enterocolitis were evaluated. Nutritional assessment, breath hydrogen testing, intestinal permeability, fecal calprotectin, serum flagellin- and lipopolysaccharide-specific antibody titers, and proinflammatory cytokine concentrations (tumor necrosis factor-alpha [TNF-alpha], interleukin-1 beta, -6, and -8) were performed at baseline and at 60 and 120 days. Healthy, age-matched control subjects (n = 5) were recruited. RESULTS BSI incidence was high (80%), and SBBO was common (50%). SBBO increased the odds for BSI (>7-fold; P = .009). Calprotectin levels were higher in children with SBS and SBBO versus those without SBBO and healthy control subjects (P < .05). Serum TNF-alpha, was elevated at baseline versus controls. Serum TNF-alpha and interleukin-1 beta, -6, and -8 levels diminished with increased enteral nutrition. Anti-flagellin and anti-lipopolysaccharide immunoglobulin G levels in children with SBS were lower versus control subjects and rose over time. CONCLUSION In children with SBS, SBBO increases the risk for BSI, and systemic proinflammatory response decreases with increasing enteral feeding and weaning parenteral nutrition.

Diverse roles of leptin in the gastrointestinal tract: Modulation of motility, absorption, growth, and inflammation

OBJECTIVE Leptin was discovered in 1994 as a hormone produced by adipose tissue with a modulatory effect on feeding behavior and weight control. Recently, the stomach has been identified as an important source of leptin and growing evidence has shown diverse functions for leptin in the gastrointestinal tract. METHODS Using leptin as a keyword in PubMed, more than 17 000 articles were identified, of which more than 500 articles were related to the role of leptin in the gastrointestinal tract. Available abstracts were reviewed and more than 200 original articles were reviewed in detail. RESULTS The available literature demonstrated that leptin can modulate several important functions of the gastrointestinal tract. Leptin interacts with the vagus nerve and cholecystokinin to delay gastric emptying and has a complex effect on motility of the small bowel. Leptin modulates absorption of macronutrients in the gastrointestinal tract differentially in physiologic and pathologic states. In physiologic states, exogenous leptin has been shown to decrease carbohydrate absorption and to increase the absorption of small peptides by the PepT1 di-/tripeptide transporter. In certain pathologic states, leptin has been shown to increase absorption of carbohydrates, proteins, and fat. Leptin has been shown to be upregulated in the colonic mucosa in patients with inflammatory bowel disease. Leptin stimulates gut mucosal cell proliferation and inhibits apoptosis. These functions have led to speculation about the role of leptin in tumorigenesis in the gastrointestinal tract, which is complicated by the multiple immunoregulatory effects of leptin. CONCLUSION Leptin is an important modulator of major aspects of gastrointestinal tract functions, independent of its more well-described roles in appetite regulation and obesity.

25-hydroxyvitamin D status of healthy, low-income, minority children in Atlanta, Georgia.

OBJECTIVES: The goals were to determine the prevalence of vitamin D deficiency among minority children in a southern US city, to examine differences in serum 25-hydroxyvitamin D levels between non-Hispanic black and Hispanic children, and to determine dietary sources of vitamin D. METHODS: Low-income, minority children (N = 290; mean age: 2.5 ± 1.2 years) were recruited during well-child clinic visits. Serum 25-hydroxyvitamin D and calcium levels were measured and dietary information was assessed. RESULTS: The mean 25-hydroxyvitamin D3 level was 26.2 ± 7.6 ng/mL, whereas 25-hydroxyvitamin D2 was not detected. Overall, 22.3% of children had deficient serum 25-hydroxyvitamin D3 levels (≤20 ng/mL), 73.6% had less-than-optimal serum 25-hydroxyvitamin D levels (≤30 ng/mL), and 1.4% had low serum calcium levels (≤9 mg/dL). A significantly larger proportion of non-Hispanic black children, compared with Hispanic children, had vitamin D deficiency (26% vs 18%; P < .05). Age and season of recruitment were significantly associated with vitamin D deficiency and low serum calcium levels. Older children (≥3 years) were less likely to have vitamin D deficiency (odds ratio [OR]: 0.89 [95% confidence interval [CI]: 0.81–0.96]; P < .001). Study enrollment during spring and summer reduced the likelihood of vitamin D deficiency by ∼20% (spring, OR: 0.85 [95% CI: 0.73–0.98]; P = .03; summer, OR: 0.82 [95% CI: 0.73–0.92]; P < .01). Fortified milk provided most dietary vitamin D (62%), with Hispanic children reporting greater intake. CONCLUSIONS: Suboptimal vitamin D status was common among apparently healthy, low-income, minority children. Age and season were significant predictors of vitamin D deficiency.

Zinc and iron deficiency and their interrelations in low-income African American and Hispanic children in Atlanta

BACKGROUND Information about the zinc status of low-income minority children in the United States is lacking. OBJECTIVE The objective was to determine the prevalence of zinc deficiency and anemia and their interrelation among low-income African American and Hispanic preschool children. DESIGN This was a cross-sectional study in which a prospective 3-d food diary was completed, and hemoglobin, serum ferritin, zinc, copper, and C-reactive protein concentrations were measured. Children with elevated C-reactive protein concentrations were excluded from analysis. RESULTS Of 292 children recruited, 280 (mean +/- SD age: 2.5 +/- 1.2 y) qualified for analysis. One hundred forty-six (52%) children were African American and 134 (48%) were Hispanic; 202 (72%) were enrolled in the Women, Infants, and Children nutrition program. A low serum zinc concentration (<10.7 mumol/L) was present in 34 (12%) children, and 37 (13%) were anemic (hemoglobin < 110 g/L). African American (odds ratio: 3.47; 95% CI: 1.51, 7.96) and anemic (odds ratio: 2.92; 95% CI: 1.24, 6.90) children had an increased risk of zinc deficiency. Serum zinc correlated with hemoglobin (r = 0.24, P < 0.001). Children with a height/length less than the fifth percentile had significantly lower mean serum zinc concentrations than those with a height/length greater than the fifth percentile (12.4 +/- 1.8 compared with 13.0 +/- 2.2 micromol/L; P < 0.001). In a multiple logistic regression model, African American race-ethnicity was associated with zinc deficiency (odds ratio: 0.26; P = 0.02). The main sources of iron and zinc in the diets were meat products and cereals. CONCLUSIONS The prevalence of zinc deficiency and anemia was high in this population of low-income minority children, especially among African Americans. Further investigation of the incidence of zinc deficiency and the ability of anemia to screen for it is warranted.

Correcting for Inflammation Changes Estimates of Iron Deficiency among Rural Kenyan Preschool Children

The assessment of iron status where infections are common is complicated by the effects of inflammation on iron indicators and in this study we compared approaches that adjust for this influence. Blood was collected in 680 children (aged 6-35 mo) and indicators of iron status [(hemoglobin (Hb), zinc protoporphyrin (ZP), ferritin, transferrin receptor (TfR), and TfR/ferritin index)] and subclinical inflammation [(the acute phase proteins (APP) C-reactive protein (CRP), and α-1-acid glycoprotein (AGP)] were determined. Malaria parasitemia was assessed. Subclinical inflammation was defined as CRP >5 mg/L and/or AGP >1 g/L). Four groups were defined based on APP levels: reference (normal CRP and AGP), incubation (raised CRP and normal AGP), early convalescence (raised CRP and AGP), and late convalescence (normal CRP and raised AGP). Correction factors (CF) were estimated as the ratios of geometric means of iron indicators to the reference group of those for each inflammation group. Corrected values of iron indicators within inflammation groups were obtained by multiplying values by their respective group CF. CRP correlated with AGP (r = 0.65; P < 0.001), ferritin (r = 0.38; P < 0.001), Hb (r = -0.27; P < 0.001), and ZP (r = 0.16; P < 0.001); AGP was correlated with ferritin (r = 0.39; P < 0.001), Hb (r = -0.29; P < 0.001), and ZP (r = 0.24; P < 0.001). Use of CF to adjust for inflammation increased the prevalence of ID based on ferritin < 12 μg/L by 34% (from 27 to 41%). Applying the CF strengthened the expected relationship between Hb and ferritin (r = 0.10; P = 0.013 vs. r = 0.20; P < 0.001, before and after adjustment, respectively). Although the use of CF to adjust for inflammation appears indicated, further work is needed to confirm that this approach improves the accuracy of assessment of ID.

Impact of liver transplantation on HRQOL in children less than 5 years old

Abstract:  Our primary goal was to assess health related quality of life (HRQOL) at transplantation and 1 yr after transplantation in pediatric liver transplant patients aged less than 5 years. We conducted a prospective longitudinal study of HRQOL in pediatric liver transplant recipients, aged less than 5 years to define the impact of liver transplantation on HRQOL and identify factors that predict HRQOL after transplantation. The infant toddler health status questionnaire (ITHQ) was completed at the time of listing for liver transplantation and at 6 and 12 months after liver transplantation. The primary outcome measures were the subscale scores that comprise ITHQ. The mean age (±s.e.m.) of the enrolled patients (n = 45) at transplantation was 1.4 (±1.2) yr. Thirty‐eight (84%) of the enrolled patients completed the study. The highest mean baseline scores of 78.6 (±3.3) were for global mental health (GlobalMH). ITHQ subscale scores increased steadily after transplantation. The greatest increase was in the first 6 months after transplant. At 1 yr after transplantation, there were significant increases in all of the ITHQ subscale scores except for GlobalMH. ITHQ subscales were similar for patients who received LDLT compared with those who received cadaver donor liver transplantation (CDLT) at baseline and a year after transplant. Time elapsed as transplantation was a significant predictor of functional health in all of the models generated. Scores for general health (GH), global health (GGH), parental time–impact (PT) and parental time–emotion (PE) were higher for male children. Family cohesion (FC) improved with time elapsed since transplant and increased number of inpatient days. HRQOL improves after transplantation in all of our patients irrespective of the donor type. Functional health scores were higher in patients with normal serum bilirubin at 1 yr post‐transplant. Assessment of HRQOL should be an integral part of care for liver transplant patients and their caregivers.

Comparison of indicators of iron deficiency in Kenyan children

BACKGROUND In the absence of a feasible, noninvasive gold standard, iron deficiency (ID) is best measured by the use of multiple indicators. However, the choice of an appropriate single iron biomarker to replace the multiple-criteria model for screening for ID at the population level continues to be debated. OBJECTIVE We compared ID defined as ≥ 2 of 3 abnormal ferritin (< 12 μg/L), soluble transferrin receptor (TfR; > 8.3 mg/L), or zinc protoporphyrin (ZP; > 80 μmol/mol) concentrations (ie, multiple-criteria model) with ID defined by abnormal concentrations of any of the independent candidate iron biomarkers (ferritin alone, TfR alone, or ZP alone) and TfR/ferritin index (ID, > 500). Values either were adjusted for inflammation [as measured by C-reactive protein (> 5 mg/L) and α(1)-acid glycoprotein (> 1 g/L) before applying cutoffs for ID] or were unadjusted. DESIGN In this community-based cluster survey, capillary blood was obtained from 680 children (aged 6-35 mo) for measurement of iron status by using ferritin, TfR, and ZP. RESULTS On the basis of the multiple-criteria model, the mean (±SE) prevalence of ID was 61.9 ± 2.2%, whereas the prevalences based on abnormal ferritin, TfR, or ZP concentrations or an abnormal TfR/ferritin index were 26.9 ± 1.7%, 60.9 ± 2.2%, 82.8 ± 1.6%, and 43.1 ± 2.3%, respectively, for unadjusted values. The prevalences of ID were higher for adjusted values only for low ferritin and an elevated TfR/ferritin index compared with the unadjusted values. The κ statistics for agreement between the multiple-criteria model and the other iron indicators ranged from 0.35 to 0.88; TfR had the best agreement (κ = 0.88) with the multiple-criteria model. Positive predictive values of ID based on the other iron indicators in predicting ID based on the multiple-criteria model were highest for ferritin and TfR. Receiver operating characteristic curve analysis indicated that TfR (AUC = 0.94) was superior to the other indicators in diagnosing ID based on the multiple-criteria model (P < 0.001). The inflammation effect did not appear to alter these observations appreciably. CONCLUSION TfR better estimates the prevalence of ID in preschoolers than do ferritin, ZP, and the TfR/ferritin index on the basis of multiple indexes in a high inflammation, resource-poor setting. This trial was registered at clinicaltrials.gov as NCT101088958.

Bloodstream Infections in Very Low Birth Weight Infants with Intestinal Failure

OBJECTIVE To examine pathogens and other characteristics associated with late-onset bloodstream infections (BSIs) in infants with intestinal failure (IF) as a consequence of necrotizing enterocolitis (NEC). STUDY DESIGN Infants weighing 401-1500 g at birth who survived for >72 hours and received care at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers were studied. The frequency of culture-positive BSI and pathogens were compared in infants with medically managed NEC, NEC managed surgically without IF, and surgical IF. Among infants with IF, the duration of parenteral nutrition (PN) and other outcomes were evaluated. RESULTS A total of 932 infants were studied (IF, n = 78; surgical NEC without IF, n = 452; medical NEC, n = 402). The proportion with BSI after diagnosis of NEC was higher in the infants with IF than in those with surgical NEC (P = .007) or medical NEC (P < .001). Gram-positive pathogens were most frequent. Among infants with IF, an increased number of infections was associated with longer hospitalization and duration of PN (median stay: 172 for those with 0 infections, 188 days for those with 1 infection, and 260 days for those with ≥2 infections [P = .06]; median duration of PN: 90, 112, and 115 days, respectively [P = .003]) and decreased achievement of full feeds during hospitalization (87%, 67%, and 50%, respectively; P = .03). CONCLUSION Recurrent BSIs are common in very low birth weight infants with IF. Gram-positive bacteria were the most commonly identified organisms in these infants.

Characterization of posthospital bloodstream infections in children requiring home parenteral nutrition.

BACKGROUND Home parenteral nutrition (HPN) is lifesaving for children with intestinal failure. Catheter-associated bloodstream infections (CA-BSI) are common in hospitalized patients receiving parenteral nutrition (PN), but data evaluating CA-BSI in children receiving HPN are limited. OBJECTIVE To determine the incidence and characteristics of CA-BSI in children receiving HPN. METHODS Medical records of 44 children receiving HPN during a 3-year period were reviewed. End points were CA-BSI during the initial 6 months after discharge. CA-BSI was defined as isolation of pathogens from blood requiring antimicrobial therapy. RESULTS The primary indication for HPN was short bowel syndrome (46%), and 59 BSI were documented during the initial 6 months of HPN in 29 (66%) children. Of CA-BSI, polymicrobial infections accounted for 52%; gram-positive, 29%; gram-negative, 17%; and fungal, 2%. CA-BSI incidence per 1000 catheter-days was highest during the first month posthospital discharge (72 episodes; 95% confidence interval [CI], 45.4-109.6). CA-BSI incidence density ratio for children receiving HPN for >90 days compared with those receiving HPN for <30 days was 2.2 (P < .05). Logistic regression revealed that Medicaid insurance and age <1 year were associated with increased risk for CA-BSI (odds ratio [OR], 4.4 [95% CI, 1.13-16.99] and 6.6 [1.50-28.49], respectively; P < .05). CONCLUSIONS The incidence of CA-BSI in children receiving HPN is highest during the first month posthospital discharge. Strategies to address care in the immediate posthospital discharge period may reduce the burden of infectious complications of HPN.

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.