Thursday, October 6, 2016
CONCURRENT SESSION I
1 DIFFERENTIAL METABOLIC PROFILES IN CHILDREN WITH SEVERE WASTING AND EDEMATOUS MALNUTRITION IN MALAWI
Valeria Di Giovanni1, Robert Bandsma1, Celine Bourdon1, Christian J. Versloot1, Ling Zhang1, Ling Zhang1, Wieger Voskuijl2, John Parkinson1,1Hospital for Sick Children, Toronto, ON, Canada,2College of Medicine, Blantyre, Malawi
Context: Mortality rates in children with severe acute malnutrition (SAM) remain high despite standardized rehabilitation protocols. Two forms of SAM are distinguished: marasmus and kwashiorkor. Marasmus is characterized by severe wasting, whereas kwashiorkor presents with nutritional edema and is characterized by more profound metabolic disturbances, including hypoalbumenia and a fatty liver. However, it is unknown if there are differences in the metabolic profiles between children with marasmus and kwaskiorkor and whether these differences could indicate the need for distinct clinical treatment plans for each form of SAM.
Objective: We aimed to 1) identify metabolic pathways which change due to nutritional rehabilitation and 2) determine if children with marasmus demonstrate different metabolic profiles from children with kwashiorkor.
Design: We studied 40 children with SAM (18 marasmus and 22 kwashiorkor) aged between 6 to 60 months, who were treated at Queen Elizabeth Central Hospital in Blantyre, Malawi. Using the Biocrates p180 kit for targeted metabolomics, we obtained measurements for 149 metabolites in serum at admission and prior to discharge after nutritional rehabilitation. Metabolites include 32 amino acids and biogenic amines, 14 acylcarnitines, 15 sphingolipids, 87 glycerophospholipids, and others.
Results: At admission, 8 amino acids, including 4 essential ones, differed between marasmus and kwashiorkor; these were all lower in children with kwashiorkor. However, with nutritional recovery, 17/21 amino acids were significantly increased and only tryptophan continued to be lower in kwashiorkor. Nutritional recovery increased only 4/12 biogenic amines which are related to cell cycle progression and oxidative stress. Again, kwashiorkor tended to have lower values; both kynurenine and total dimethylarginine continued to be lower in kwashiorkor compared to marasmus after nutritional rehabilitation. Sphingolipids were not altered by nutritional recovery and also did not differ between groups. At admission, most acylcarnitines (9 out of 14) were lower in kwashiorkor patients compared to those with marasmus, and 3 continued to be lower after nutritional recovery. Acylcarnitines were of particular interest as they relate to beta oxidation, energy metabolism, fatty acid transport and mitochondrial damage.
Conclusions: Many but not all metabolites increased following nutritional recovery, pointing to a restoration in metabolic homeostasis. At admission, metabolites levels that differ between the two forms of SAM are systematically lower in children with kwashiorkor. In particular, lower levels of acycarnitines in kwashiorkor patients point to potentially impaired beta oxidation of fatty acids, which can be a source of energy during malnutrition. Our results suggest that specific metabolic disruptions may underlie the different clinical manifestation of marasmus and kwashiorkor and could be the basis for differential targeted treatments.
2 ACTIVATION OF CALCIUM-SENSING RECEPTOR IN THE GUT INHIBITS ENTEROTOXIN-INDUCED SECRETION AND BACTERIA-INDUCED INFLAMMATION IN RODENTS AND REDUCES INFECTIOUS DIARRHEAS IN CHILDREN
Sam Cheng1, Lieqi Tang1, Shi Jin1, Steven Winesett1, Henry Binder2,1University of Florida, Gainesville, FL, USA,2Yale University, New Haven, CT, USA
Introduction: Treatment of infectious diarrheas remains a challenge globally, particularly in infants, young children, and immune-compromised patients. Children with infectious diarrhea who become dehydrated are normally treated with oral or intravenous rehydration. Although rehydration can replace the loss of fluid, it neither stops ongoing intestinal secretion nor does it reduce underlying gut inflammation. Therefore, there has been continuous effort to search for new cost-effective ways to safely stop diarrhea. The extracellular calcium-sensing receptor (CaSR) is a unique Class C G protein-coupled receptor that uses nutrients such as calcium, polyamines and aromatic amino acid as its ligands. Recent studies indicate that CaSR is highly expressed in the gut, and when activated by selective nutrients or specific chemical agonists, exhibits unusual pro-absorptive, anti-secretory, and anti-inflammatory properties. We therefore hypothesized in the present study that activating CaSR in the gut reduces secretory and inflammatory diarrheas.
Methods: To test this hypothesis, three models of diarrhea were induced in 4–6 week-old Sprague-Dawley rats and/or C57BL/6 mice (CaSR wild-type and knockout), and the effects of CaSR agonists calcium, spermine, tryptophan, and R568 were examined. These included 1) cholera toxin model of secretory diarrhea; 2) citrobacter model of infectious diarrhea; and 3) dextran sodium sulfate (DSS) model of inflammatory diarrhea. To further prove the concept, antidiarrheal effect of calcium, primary ligand of CaSR, was also assessed on patients with viral, bacterial, and/or parasitic enterocolitis.
Results: Mice receiving cholera toxin gavage developed secretory diarrhea; the latter was inhibited by R568 i.p. in wild-type but not in CaSR null mice. Similarly, mice receiving C. rodentum gavage or DSS treatment developed inflammatory diarrhea, which was significantly more severe in knockout mice than the wild-type controls. Increasing dietary calcium reduced the severity of diarrhea in wild-type mice; such an effect was not seen in CaSR mice. In rats, activation of CaSR by dietary calcium significantly delayed the onset, reduced the severity, and accelerated the recovery of DSS-induced colitis; so did dietary spermine and dietary tryptophan. Finally, five patients with infectious enterocolitis who developed severe diarrhea and hypocalcemia were selected to receive calcium replacement therapy. As calcium therapy continued and hypocalcemia improved, stool output decreased; when serum calcium levels normalized, diarrhea stopped.
Conclusion: These results suggest that targeting intestinal CaSR with nutrients, alone or in combination, may represent a new cost-effective method to stop diarrhea and treat inflammation in children. Clearly, randomized controlled trials are warranted.
3 ROTAVIRUS IMMUNIZATION: GLOBAL COVERAGE AND LOCAL BARRIERS FOR IMPLEMENTATION
Andrea Lo Vecchio1, Alfredo Guarino1, Jorge Amil Dias2, James A, Berkley3, Chris Boey4, Mitchell B. Cohen5, Sylvia, Cruchet6, Eduardo Salazar-Lindo7, Sandhu Bhupinder8, Philip Sherman9, Toshiaki Shimizu10, Ilaria Liguoro1,1University of Naples Federico II, Naples, Italy, Italy,2Hospital de São João, Porto, Portugal,3KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya,4University of Malaya, Kuala Lumpur, Malaysia,5University of Alabama at Birmingham, Birmingham, AL, USA,6INTA, Universidad de Chile, Macul, Chile,7Universidad Peruana Cayetano Heredia, Lima, Peru,8Bristol Royal Hospital for Children, Bristol, UK,9Hospital for Sick Children, University of Toronto, Toronto, ON, Canada,10Juntendo University Graduate School of Medicine, Tokyo, Japan
Background: Since 2006 two effective and safe vaccines against rotavirus (RV) infection (Rotarix™ and RotaTeq®) have been recommended by WHO worldwide. In 2012, FISPGHAN identified the spreading of RV immunization (RVI) as a top priority for the control of diarrheal illness in childhood.
Aims: FISPGHAN Working Group (WG) on acute diarrhea aimed at estimating the current RVI coverage and identifying the major barriers to local implementation in all countries of the world.
Methods: A survey was distributed to national experts in infectious diseases and vaccinations between March 2015 and April 2016. The survey provided information on the inclusion of RVI in the National Immunization Plan, presence of RVI programs, costs and perception of local barriers to implementation.
Results: Among the 76 countries contacted, 44 provided a survey eligible for analysis (response rate 58%). RVI is recommended in 23/44 countries (52.3%) participatingin the survey. Although five countries have recommended RVI since 2006, most (13/44, 29.5%) included RVI in National Immunization Schedule between 2012 and 2014. The costs of vaccination are covered by the government (38.6%), by the GAVI Alliance (9%) or public and private insurances (6.8%) in some countries. However, in most cases, those costs are charged to families (43.1%).
The limited perception of RV severity by families (50%) and elevated costs (45.4%) are the major barriers for large-scale implementation of RVI program. Surprisingly, only 6 countries (13.6%) reported the timing of first administration within 6 weeks as a major barrier.
Conclusion: After approximately 30 years since the introduction of RVI, the implementation of this major life-saving intervention is still unacceptably low and remains a major target for reaching the Millennium Developmental goal.. To sustain and implement RVI, FISPGHAN could promote education for families/caregivers and physicians focused on the risk of RV diarrhea and efficacy of immunization.
4 THE EFFECT OF TWO PROBIOTIC STRAINS BB-12® and LGG® ON DIARRHEA IN CHILDREN WITH SEVERE ACUTE MALNUTRITION IN UGANDA
Benedikte Grenov1, Hanifa Namusoke2, Betty Lanyero2, Nicolette Nabukeera-Barungi3, Christian Ritz1, Christian Mølgaard1, Henrik Friis1, Kim F. Michaelsen1,1University of Copenhagen, Copenhagen, Denmark,2 Mulago National Referral Hospital, Kampala, Uganda,3Makerere University, Kampala, Uganda
Globally, undernutrition is the cause of approximately 3.1 million child deaths annually. Diarrhea is a major cause of morbidity and mortality in undernourished children. Probiotics seem to reduce duration of diarrhea in children, but results have mainly been obtained in well-nourished children in high-income countries. We aimed at investigating the effect of probiotics on diarrhea in children with severe acute malnutrition (SAM) during in- and outpatient treatment in a low-income country.
A randomized, double-blind, placebo-controlled study was carried out in 400 children admitted with SAM. Children received one sachet daily with a mixture of BB-12® and LGG® (10 billion colony-forming units/sachet, 50:50) or placebo during hospitalization and subsequent outpatient treatment for 8 – 12 weeks. The primary outcome was number of days with diarrhea during inpatient treatment. Secondary outcomes included number of days with diarrhea during outpatient treatment, diarrhea incidence and severity, pneumonia incidence, duration and severity, days with fever or vomiting, weight gain and recovery. All outcomes were analyzed separately for in- and outpatient treatment. Diarrhea data was collected using a stool diary in which caregivers noted every time their child passed stool and categorized the stool consistency according to a 4-point photo scale.
There was no difference in number of days with diarrhea during inpatient treatment for the probiotic vs. the placebo group (adjusted difference +0.2 days, 95% CI -0.8 to 1.2 days, p
= 0.69). However, during outpatient treatment the number of days with diarrhea was reduced in the probiotic group compared to the placebo group by 26% (adjusted difference -2.2 days, 95% CI -3.5 to 0.3, p
= 0.025). There was no significant effect of probiotics on diarrhea incidence or severity, pneumonia outcomes, fever, vomiting, weight gain or recovery. Although not significant, some outcomes related to infections occurred less frequently in the probiotic group during outpatient treatment (diarrhea incidence odds ratio (OR) 0.7 (0.4 to 1.2), p
= 0.17, pneumonia incidence OR 0.5 (0.2 to 1.3), p
= 0.17, fever -0.5 days (-1.3 to 0.2 days), p
= 0.16). Mortality was 13% (n = 26) in the probiotic and 10% (n = 20) in the placebo group (p
LGG® and BB-12® did not reduce diarrhea during inpatient treatment of children with SAM, but reduced the number of days with diarrhea during outpatient treatment. This result is in line with a study testing a mixture of pro- and prebiotics in children with SAM which reported no effect of the intervention during inpatient treatment but a trend towards reduced mortality during outpatient treatment. Probiotics may have a future role in outpatient treatment of children with SAM.
5 ENVIRONMENTAL ENTERIC DYSFUNCTION IS ASSOCIATED WITH POOR LINEAR GROWTH AND CAN BE IDENTIFIED BY HOST FECAL mRNAs
M. Isabel Ordiz, Mark J Manary, Nurmohammad Shaikh, Indi Trehan, Phillip I Tarr, Washington University in Saint Louis School of Medicine, St. Louis, MO, USA
Background and Objective: Environmental enteric dysfunction (EED) can be assessed by the lactulose:mannitol (L:M) test. Our objective was to determine if selected host fecal transcripts were correlated with EED, and whether transcripts and clinical characteristics could be used to predict EED in rural African children.
Methods: Demographic and sanitation characteristics, along with L:M testing and host fecal transcript analyses from 798 asymptomatic Malawian children aged 12–61 months were compared to linear growth over the subsequent 3 months. Fecal host mRNA analysis included quantification of expression of 18 transcripts associated with L:M. Permeability was categorized as normal (L:M ≤0.15), moderate (0.15 < L:M < 0.45) and severe (L:M ≥ 0.45), and random forest predictive models were created.
Results: L:M was inversely correlated with linear growth over the subsequent 3 months (r -0.32, p < 0.001) and severe EED was associated with stunting (p < 0.0001). Age <24 months, weight-for-height Z-score <0, domesticated animals in the child's sleep environment, lack of a pit latrine or clean water source, and a recent history of diarrhea were associated with severe EED. A random forest model using CD53, HLA-DRA, MUC12 and TNF was 84% sensitive for severe EED and 83% sensitive for no EED.
Conclusion: Selected host fecal transcripts can be used in a random forest model as a non-invasive biomarker for categories of EED in rural African children.
6 ASSESSING THE IMPACT OF MATERNAL EXPOSURE TO DROUGHT ON CHILD GROWTH
Thokozani E. Phiri, University of Waterloo, Waterloo, ON, Canada
Early childhood adversity that impacts the growth of mothers in their childhood may negatively influence the growth outcomes of their young offspring. Famine studies in Holland and China have shown the impact of epigenetics. A study in Malawi investigates this phenomenon in the context of three meteorological droughts (1981, 1987, and 1992 respectively) and women residing in rural and peri-urban Mangochi district. A hypothesis is tested that there was a difference in mean LAZ, mean WAZ, and mean birthweight between children born to drought exposed mothers and children born to non-exposed mothers.
Being a natural experiment, women were already pre-selected into groups of those exposed and not exposed to three different droughts (1981, 1987, and 1992 respectively) by virtue of their date of birth (DOB). This retrospective cohort study used children's neonatal size measurements taken during a randomized controlled trial (iLiNS-DYAD-M). Their mean birthweight, mean LAZ, and mean WAZ were the outcomes (n = 1403 includes 12 twins) while their mothers’ environmental experience of drought was the exposure (n = 1391). Some of the covariates were child sex and the maternal variables of education, height, BMI, marital status, sole head of household, “at risk” during pregnancy, and primiparity at “at risk” ages.
LAZ, WAZ and birthweight were positively associated with mother's exposure to the drought of 1987 even with covariate analysis (p < 0.01) except for the birthweight which no longer showed statistically significant results. The droughts of 1981 and 1992 as independent variables were not associated with the study outcomes at any level of significance (alpha 0.01; 0.05; 0.1) even when covariates were added to the models. The covariates that were associated with LAZ and WAZ in the 1987 drought model were maternal height, being both a mother and head of household, and being an older or younger “at-risk” mother who was primiparous. Only maternal height had a positive association (p < 0.01). Older mothers (age >35 yr) or younger mothers (age >18 yr) deemed “at-risk” during pregnancy were more likely to have children with a relatively lower LAZ and WAZ than mothers who were not at risk as did mothers who were heads of household.
The 1987 drought appears to be different to the other droughts in that there were some noteworthy associations. It has been historically noted as being moderate while the 1992 one was the worst of the three; however, major drought relief efforts were implemented and offset much of the impact. In terms of the puzzling positive association observed with the 1987 drought and LAZ or WAZ, epigenetics may have played a role as reported in studies on the Great China Famine and the Dutch Famine. In sum, the present study may provide additional evidence for the reversal of the negative intergenerational impact of early childhood adversity.
Thursday, October 6, 2016
POSTER SESSION I
12:00 – 2:00 PM
∗ Poster of Distinction
CELIAC AND OTHER LUMINAL DISORDERS
23 EOSINOPHILIC ESOPHAGITIS IN CHILDREN: A RETROSPECTIVE COHORT STUDY
Ajay Sharma, Neha Chawla, SJOG Midland Hospital, Perth, Western Australia
Short title: Pediatric Eosinophilic Esophagitis.
children, eosinophilic esophagitis, and intervention.
Background: Eosinophilic esophagitis (EoE) is a chronic allergy/immune-mediated disease with significant morbidity. It is characterized by dense eosinophilic infiltration of esophageal epithelium. EoE is increasingly recognized in children with high prevalence in patients with atopic disease.
Objective: To report our experience in children with EoE.
Methods: We conducted a retrospective cohort study using prospectively collected data in children (0–18 years) with an eosinophilic esophageal disorder between July 2014 and October 2015. Clinical characteristics including personal and family history for allergy, peripheral eosinophilia and IgE levels, endoscopic and histologic findings, treatment details, and outcomes were studied.
Results: A total of 31 children were diagnosed with EoE during the short study period (mean age: 7.6 years; 24 males and 7 females). Presenting symptoms varied with age; 12 had atopic condition. On endoscopy, 29/31 had abnormal appearing esophageal mucosa. Linear furrowing and mild erythema were the most common endoscopic findings. The treatment included topical steroids and/or dietary therapy.
Conclusion: Our experience indicates that the diagnosis of eosinophilic esophagitis in children is on the rise, presenting symptoms vary with age and has a common pathophysiological background with allergy as reported in previous studies. Identifying causative allergen and monitoring response to treatment remains problematic. Treatment options include topical steroids or avoidance of food allergen. Dietary therapy, though safe, lacks strict compliance.
24 ASSESSMENT OF RELIABILITY OF PLASMA CITRULLINE AND I-FABP AS NON-INVASIVE MARKERS OF ENTEROPATHY: A STUDY IN A HUMAN MODEL
Alka Kumari1, Govind K Makharia1, Anil K Verma2, Università Politecnica delle Marche, Ancona, Italy, Shyam Prakash1, Prasenjit Das1, Mona Pathak1, V Sreenivas1, Vineet Ahuja1, Lalit Kumar1,1All India Institute of Medical Sciences, New Dehli, India,2Università Politecnica delle Marche, Ancona, Italy
Background/Aim: There is a need for non-invasive biomarker of enteropathy both for diagnosis and monitoring of enteropathic diseases such as celiac disease. Assessment of plasma citrulline and plasma levels of intestinal fatty acid binding protein (I-FABP) have been proposed, but their reliability is yet not confirmed. For confirmation of reliability of these markers, we used a model [patients with hematological malignancies receiving myeloablative therapy for hematopoietic stem-cell transplantation (HSCT)] where changes occur cyclically in rapidly dividing cells with myeloablative therapy.
Patients and Methods: Seventy adult patients with hematological malignancies receiving myeloablative therapy for HSCTs were recruited. Plasma samples were collected at different time-points i.e., before and after transplantation on HSCT days -7, -5, -1, 0, +7, +15 and +28. Levels of plasma citrulline (by HPLC), I-FABP (by commercially available ELISA) and total leukocytes counts were measured at each point of time.
Results and discussion: Concentration of citrulline in plasma decreased significantly and consistently below the baseline at day+7 (p < 0.001), and its level rose gradually at day +15 and day+28. The concentration of I-FABP fluctuated between day +7 and day+15 and then it rose at day +28. The decrease in level of plasma citrulline followed similar pattern as observed by total leucocytes count in peripheral blood.
Conclusions: The data suggests that plasma concentration of citrulline follows pattern of cyclical changes in enterocyte mass as induced by myeloablative therapy. Therefore, an assessment of plasma level of citrulline may prove to be a reliable marker of enterocyte mass.
25 PERSISTENT BASAL CELL HYPERPLASIA IN INACTIVE EOSINOPHILIC ESOPHAGITIS: IS INACTIVE REALLY INACTIVE?
Bridget C. Godwin1, Hiroshi Nakagawa2, Kelly Whelan2, Ben Wilkins1, Alain J. Benitez1, Maureen DeMarshall2, Gary Falk2, Jonathan Spergel1, Amanda B. Muir1,1The Children's Hospital of Philadelphia, Philadelphia, PA, USA,2University of Pennsylvania, Philadelphia, PA, USA
Background and Aims: Eosinophilic esophagitis (EoE) is a chronic, antigen and immune-mediated esophageal disease characterized by symptoms such as dysphagia and food impaction. Histologic changes in active EoE include a peak eosinophil count of ≥ eosinophils per high-power field (eos/hpf) and basal cell hyperplasia (BCH) in esophageal mucosa. According to current diagnostic criteria, EoE transitions from active disease to inactive disease when the peak eosinophil count drops below 15 eos/hpf, typically following therapeutic intervention. We aimed to evaluate BCH in EoE patients with inactive disease in relation to eosinophil count as well as patient-reported symptoms within 30 days prior to biopsy.
Methods: Pediatric and adult histology from an IRB-approved patient repository of esophageal biopsies was reviewed by a pathologist specializing in gastroenterology. Specimens were scored for eosinophils and BCH. These data were then correlated with clinical data obtained at time of endoscopy through the same IRB-approved study, specifically presence of symptoms within 30 days of endoscopy. 304 pediatric and 137 adult specimens were scored from a total of 204 pediatric and 107 adult patients. Patient age ranged from 1–66 years, with 75% of patients being male. Of the specimens reviewed and included for analysis, 52 were from non-EoE patients, 221 from patients with inactive EoE, and 74 from patients with active EoE. 94 patients were excluded from analysis given unclear diagnosis or status at time of endoscopy.
Results: Scoring revealed the presence of BCH (defined as basal cells that reached >20% of epithelial height) in 5.8% (n = 52) of non-EoE patients, 24.9% (n = 221) of inactive EoE patients, and 97.3% (n = 74) of active EoE patients. Average BCH score was significantly higher in patients with inactive EoE than in non-EoE (p
= 0.0024). Eosinophil count in inactive EoE was significantly higher with persistent BCH (n = 55, average eos/hpf 6.9 = 0.62) than without (n = 166, average eos/hpf 2.2 +/- 0.25) (p < 0.0001). In the inactive EoE cohort, symptoms such as heartburn, dysphagia and regurgitation were more prevalent in patients with BCH (53.7%, n = 67) than patients without BCH (30.4%, n = 07) (p
Conclusions: BCH persists in patients with EoE that is clinically defined as inactive. Persistent BCH correlates with patient symptoms and eosinophil burden in inactive EoE patients. These findings suggest that BCH may be used to evaluate symptoms in patients with inactive EoE. Although current clinical EoE guidelines define inactive EoE disease as <15 eos/hpf present on esophageal biopsies, our data suggest that a lower eosinophil count than 15 may be necessary to truly define inactive disease. Further studies regarding basal cell hyperplasia and its role in inflammation and barrier defect will further characterize the importance of re-defining inactive disease.
26 CAESAREAN SECTION AND COW'S MILK PROTEIN ALLERGY (CMA): IS IT A RISK FACTOR IN ARGENTINE INFANTS?
Christian Boggio Marzet, Tilli María Anabel, Basaldúa María Teresa, Pirovano Hospital, Caba, Buenos Aires, Argentina
Introduction: CMA is a continually growing disorder. Several studies suggest that babies delivered via vaginal canal acquire the mother's vaginal microbiota, which may help protect them and promote a healthy immune system’ however, babies born via Caesarean section acquire bacteria from the hospital environment that may increase the risk of food allergies and other problems.
Aim: To evaluate Caesarean section as a risk factor to develop different forms of CMA presentation.
Methods: All children from 2010–2014 who were referred to the Pediatric Gastorenterology Section at Pirovano Hospital with a diagnosis of CMA were included. Treatment was provided depending on the treating physician. Medical records were used to recruit by sex, age, birth weight, gestational age, clinical presentation of CMA and type of delivery.
Results: 238 patients were included. Mean age 0.60 months ± SD 0.97 (range 0–48–0.72). Females 50.8%. Mean gestational age: 38.38 weeks ± SD 1.72 (range 32–42). Mean birth weight: 3.149 gr ± SD 595.19 (range 2.936–4.355). Clinical presentation: rectal bleeding (RB) 44.5%, reflux (GER) 19.3%, immediate reactions (IMM) 14.3%, enteropathy (ENT) 11.8% and colic (COL) 10.1%. Type of delivery: Caesarean 56.3%, vaginal 43.7%. No statistical significant differences were found between type of delivery and clinical presentation (p
= 0.70), type of delivery and sex (p
= 0.28) and sex and clinical presentation (p
= 0.62) (Chi square Test). A positive risk correlation was found between IMM and Caesarean section (OR 1.45 95% CI, 0.69–3.04) and between GER and COL and Caesarean section (OR 1.26 95% CI, 0.65–2.43 and OR 1.33 95%CI 0.55–3.17 respectively).
Conclusions: Caesarean section was found to be a risk factor for developing not only IMM but also delaying the reactions (GER and COL) of CMA.
∗27 ANTI-TISSUE TRANSGLUTAMINASE NORMALIZATION POST DIAGNOSIS IN CHILDREN WITH CELIAC DISEASE.
Daniela Migliarese Isaac1, Seema Rajani1, Maryna Yaskina2, Hien Q. Huynh1, Justine M. Turner1,1University of Alberta, Edmonton, AB, Canada,2Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada,
Introduction: Celiac disease (CD) is a common autoimmune enteropathy to gluten, leading to intestinal inflammation, villous atrophy, and malabsorption. CD screening involves anti-tissue transglutaminase (atTG) IgA levels, followed by intestinal biopsy for confirmation. A gluten-free diet (GFD) is required to alleviate symptoms, normalize atTG, and heal the intestinal mucosa in CD patients. CD monitoring includes following atTG titers post diagnosis. Limited pediatric studies exist examining the trend of atTG normalization, with no studies examining predictors of atTG over time in children with CD. We aimed to evaluate time to normalization of atTG in children post CD diagnosis, and to assess for independent predictors impacting this time.
Methods: A retrospective chart review was completed to evaluate atTG normalization time in pediatric CD patients diagnosed from 2007 to 2014 in the Stollery Pediatric Celiac Clinic (Edmonton, Alberta, Canada). The following clinical predictors were assessed for impact on time to normalization: initial atTG, Marsh score at diagnosis, GFD compliance (GFDC), age at diagnosis, gender, ethnicity, medical comorbidities, and family history of CD. Kaplan-Meier survival analysis was completed to assess time to atTG normalization, followed by Cox hazard regression to assess for independent predictors of atTG normalization time.
Results: 487 of 616 patients reviewed met inclusion criteria. Mean age was 9.3 years at diagnosis, with 64% females. Patients were followed from 6 months to 6 years. 80.5% of patients normalized atTG levels within the study time period. Median time to normalization was 407 days for all patients (95% CI [361–453]), and 364 days for GFD compliant patients (95% CI, [335–393]). Type 1 diabetes mellitus (T1DM) patients took significantly longer to normalize at 1204 days (95% CI, [199–2209], p < 0.001). Ethnicity was associated with longer time to normalization, with South Asians (SA) taking 809 days (95% CI, [262–1356], p
= 0.001); however, the validity was poor due to wide differences in censoring between ethnicities (Caucasian 18.2%, SA 35.2%). T1DM (HR 0.363 [0.238–0.553], p < 0.001) and higher baseline atTG (HR 0.999 [0.999–1], p < 0.001) were significant predictors of longer time to atTG normalization on Cox hazard regression. Conversely, GFDC was a significant predictor of earlier normalization (OR 13.91 [7.859–24.621], p < 0.001). The remaining variables assessed were not significant.
Conclusions: There is wide variation of rate and time to atTG normalization in children with CD. GFDC and lower atTG at diagnosis are predictors of earlier normalization. Patients with T1DM are less likely to normalize atTG levels, and have longer time to normalization. There may be an association between SA ethnicity and longer duration to normalization, but the validity of this finding is poor due to wide differences in censoring. Overall, there is a need for closer attention and education for these higher-risk populations.
28 IS CANDIDA DETECTED IN DUODENAL BRUSHINGS CLINICALLY SIGNIFICANT?
Devendra I Mehta, Daniel Sanchez, Nishant Patel, Jeffrey Bornstein, Karoly Horvath, Jessica Bonilla, Chirajyoti Deb, Orlando, FL, USA
Background: Recent studies support a role of small intestinal fungal overgrowth (SIFO) in adults with IBS disease symptoms, immunocompromised or not. Commensal candida density has been reported to be <100 cfu/mL. We aimed to find the clinical significance of Candida detected by duodenal brushings in children undergoing diagnostic endocopy, and assess histology, candida staining, and mucosal disaccharidases to look for evidence of pathology.
Methodology: Out of a total of 111/1900 studies had had Candida overgrowth (>1000 cfu/mL cfus) had their mucosal histology, associated diagnostic findings, and disaccharidase activity assessed in comparison with those without Candida. A subset of duodenal biopsy samples were examined microscopically with hematoxylin and eosin (H&E) and special periodic acid shift with diastase (PASD) staining. Statistical analyses between SIFO and 2500 sequential disaccharidases were done using IBM SPSS.
Results: One hundred eleven patients (age: 0 to 20+ years; female 61) had fungal overgrowth with differential counts ranging from 1 to 300x10^3 CFU/mL. Most of the fungal species were Candida but one had Trichosporon asahii overgrowth. Combined fungal and bacterial overgrowth (> 10^4) was present in 57 patients. 12 (12/111) patients had abnormal histology of which 3 (3/12) had focal villous blunting without any other known cause. 2 of these 3 samples revealed increased intraepithelial lymphocytes. 3 samples exhibited chronic duodenitis and one had Crohn's disease. An examination of 30 patients with a PASD stain revealed no evidence of candida hyphae. Of these 33/111 patients with fungal overgrowth had normal disaccharidase activity, compared with 1454/2489 entire population (p < 0.000), 17/111 had generalized depression compared with 124/2489 (p < 0.000), 35/111 had lactase deficiency compared with 1045/2849 population (p < 0.05).
Conclusion: Duodenal brushing sample was found to be suitable to detect fungal over growth at a threshold level of 1000 CFU/mL. Fungal overgrowth was caused by different Candida species. A significant number of patients with fungal overgrowth were found to have generalized depressed activities of all the disaccharidases and many of them have lactase deficiencies separate from generalized depression of disaccharidases compared with population rates. However, direct staining using PASD in a subgroup of 30 did not show evidence of invasion/ hyphae. Further studies are warranted to evaluate the association of fungal overgrowth and disaccharidase deficiencies and IBS symptoms.
29 INCREASED INTESTINAL MAST CELLS IN CHILDREN WITH CHRONIC ABDOMINAL PAIN
Sarah Donnelly1, J. Antonio Quiros1, Christine Carter-Kent1, James Marcin2, Yunru Huang2, Shaoli Sun1, Johanna Palmadottir1,1MUSC Children's Hospital, Charleston, SC, USA,2University of California - Davis Children's Hospital, Sacramento, CA, USA
Mast cells are immune cells that secrete vasoactive mediators (histamine, tryptase) and are usually associated with anaphylactic responses. Increased numbers of mast cells have been found in both adults and pediatric patients with chronic abdominal pain. Mast cell activity has been recently linked with enteric nerve proliferation due to neuronal growth factors but its role in functional abdominal pain is unclear. There is currently limited research on determining the characteristics of pediatric patients with abdominal pain and increased intestinal mast cell counts, risk factors and outcomes to treatment.
Objective: To determine if there are any generalizable characteristics for pediatric (<18y) patients experiencing recurrent abdominal pain with increased gastrointestinal mast cell counts in order to better determine disease risks and outcomes from therapy.
Methods: We performed a retrospective study of all children and adolescents with abdominal pain who had staining to assess mast cell (MC) burden (n = 42). MC specific stains (CD117) were requested in cases of refractory abdominal pain, with a history of headaches, flushing or hives. Non-parametric data on these patients was then gathered by chart review. Characteristics such as age, race, weight, allergy history, and location of residency were collected. Also treatment data and symptom reporting was collected for all subjects. We then ran statistical analyses to determine if any factors seemed to be a determinant of the presence of increased mast cell counts in intestinal biopsies, their anatomic location, and the prevalence of allergic disorders and response to treatment.
Results: From our sample population, 83% (n = 35) of patients met biopsy criteria for increased mast cell presence (>20 MC/hpf) in at least one biopsy sample. Of these patients, 90.5 percent were white and 9.5 percent were black. There was a female predominance within the group at 64 percent. A large proportion of these patients were underweight (36%) and this was statistically significant in patients with colonic involvement (p-value 0.02). Of those patients who received allergy testing, 60 percent had positive results. 71% of positive patients were treated with either an H1 or H2 blocker, mast cell stabilizer, or leukotriene inhibitor and 68% of these had symptom improvement.
Conclusion: The presence of clinical symptoms of mast cell activation in children and adolescents with chronic abdominal pain appears to be a significant indication for performing mast cell staining on biopsy. While typical hematologic markers for mast cell activation do not seem to correlate to increased GI mast cell presence, allergy testing may be indicated in those with positive biopsy results. Existing treatment options appear to have a substantial effect on symptom improvement but standardization of treatment strategies could enhance treatment outcomes and this might be an area for new drug development.
30 WHERE DID ALL OF THE INFANT SPITTERS GO? DIAGNOSES OF INFANT GERD, REGURGITATION, VOMITING AND COLIC IN GENERAL PEDIATRIC PRACTICE
JP Franciosi1, LN Werk1, LK Handy1, J Crutchfield2, L Ingraham2, MC Diaz3, RA Gomez-Suarez1, J Hossain3, T Wysocki4,1Nemours Children's Health System, Orlando, FL, USA,2Lockheed Martin Corporation, Orlando, FL, USA,3Nemours Children's Health System, Wilmington, DE, USA,4Nemours Children's Health System, Jacksonville, FL, USA
Infant gastroesophageal reflux (GER) is a common physiologic process that is frequently not distinguished from true infant gastroesophageal reflux disease (GERD). Non-adherence to clinical guidelines leads to over-diagnosis of gastroesophageal reflux disease, misdiagnosis of other conditions, over prescribing unnecessary medications and unnecessary medical testing. We conducted a retrospective electronic medical record review across the Nemours Children's Health System's general pediatrics practices over a 6 month period between 10/01/2015–3/31/2016 comprising 120 providers, 6249 unique infants and 21,823 total visits among infants 6 months of age or less. Among 919 unique infants with 1372 encounters over the time period, primary care practitioners recorded the following ICD-10 diagnoses: regurgitation (6.9%, 94 diagnoses/1,372 total encounters); GERD (55.8%, 766 diagnoses/1372 total encounters), other vomiting (5.5%, 75 diagnoses/1,372 total encounters); and colic (7.4%, 102 diagnoses/1372 total encounters). Proton pump inhibitor (PPI) medications were prescribed in 5.7% (52/919 unique infants) and H2 receptor antagonist (H2RA) were prescribed in 0.5% (5/919 unique infants). Among 18 upper GI radiology tests and 42 pyloric ultrasounds, 94.4% and 50.0% were respectively ordered for a diagnosis of GERD only. Infants were frequently given a diagnosis of GERD over regurgitation or colic, and PPI medications were prescribed for infants inconsistent with guidelines. We propose these findings indicate a gap between actual decision making and the widely disseminated AAP Clinical Report and the NASPGHAN Consensus Guidelines. An intervention to ensure clinicians are educated around best practices and that the knowledge is retained over time is discussed. We will explore the impact of promoting knowledge retention on decision making related to diagnosis, prescription of medications and request for medical testing.
∗31 THE L2-IL5(OXA) MOUSE: A NOVEL MODEL OF CHRONIC FIBROSTENOTIC EOSINOPHILIC ESOPHAGITIS
Joanne Masterson1, Kathryn A. Biette1, Juliet A. Hammer1, Eoin N. McNamee1, Kelley E. Capocelli2, James J. Lee3, Glenn T. Furuta2,1University of Colorado Denver, Aurora, CO, USA,2Children's Hospital Colorado, Aurora, CO, USA3Mayo Clinic, Scottsdale, AZ, USA
Background: Dysphagia, stricture and food impactions are common symptomatic consequences for eosinophilic esophagitis (EoE) patients. However, to date limited understanding of the pathophysiologic mechanisms of remodeling in EoE exits. We hypothesized that a hypersensitivity reaction with prolonged and localized eosinophilic inflammation in mice would lead to esophageal remodeling similar to that observed in EoE patients.
Methods: Transgenic mice overexpressing the eosinophilopoietin IL-5, selectively in the esophageal epithelium (L2-IL5), were sensitized and challenged with oxazolone 9 times/29 days (chronic: L2-IL5-OXA-C) and compared to a previously published EoE model where mice are challenged 3 times/8 days (acute: L2-IL5-OXA-A). Treatment with Dexamethasone (Dex: 200ug/ms i.p.) 3 times/week was used as a therapeutic intervention. H&E stained esophagi were evaluated using a histological score (index of epithelial inflammation [eosinophil & chronic inflammatory infiltrate], epithelial remodeling [basal zone hyperplasia (BZH), dilated intracellular spaces, hyperkeratosis], internal esophageal layer fibrosis and intramuscular inflammation. Immunohistochemistry was performed evaluating fibrosis (Massons Trichrome) and proliferation/BZH (Ki67). Esophageal tissues were processed for Taqman mRNA analysis, and immune cell infiltrates were characterized by flow cytometry.
Results: Significant esophageal histopathological alterations were observed in the L2-IL5-OXA-C mice compared to L2-IL5-OXA-A counterparts, including eosinophilia (6 vs. 3.8, P 0.01) microabscesses (1 vs. 0.75, p
= 0.1) and basal zone hyperplasia (BZH) (2.8 vs. 2, p < 0.001). Increases in dilated intercellular spaces (DIS) (3.2 vs. 0.5, p < 0.001) and internal esophageal layer fibrosis (IELF) (5.6 vs. 1, p < 0.001) were observed in L2-IL5-OXA-C mice compared to L2-IL5-OXA-A. The overall histological score was significantly higher in L2-OXA-C mice (22.6 vs. 11.8, p < 0.001). L2-IL5-OXA-C mice had increased Trichrome staining and expression of fibrotic remodeling genes including COL1A1 (3-fold, p < 0.05) and COL4A1 (7-fold, p < 0.05), while barrier dysfunction was indicated by decreased CLDN1 expression. Flow cytometry confirmed a significant increase is esophageal eosinophilia in L2-IL5-OXA-C mice compared to L2-IL5-OXA-A (14.5x10^5 vs. 1.15x10^5, p < 0.05). Treatment with dexamethasone significantly attenuated histopathologic indices (3.8 vs. 22.6, Dex vs. Saline, p < 0.001), including eosinophilia, DIS and fibrosis. Of note, Ki67 immunohistochemistry indicated a significant decrease in BZH (15 vs. 66 cells/hpf, p < 0.001). Eosinophilic chemokines CCL11 (80%) and CCL24 (93%) were decreased and tight junction molecules CLDN1 (5-fold, p < 0.05) and CLDN7 (15-fold, p < 0.001) were increased indicating restored barrier.
Conclusion: Collectively, these studies identify the L2-IL5OXA mouse as a novel preclinical model to study the epithelial barrier dysfunction, fibrosis and remodeling associated with chronic EoE.
32 EOSINOPHILIC ESOPHAGITIS OCCURRING IN CHILDREN WITH CYSTIC FIBROSIS: A CASE SERIES
John Pohl1, Raphael Firszt1, Barbara Chatfield, Fadi Asfour1, Catherine McDonald2, Amy Lowichik1,1University of Utah, Salt Lake City, UT,2Primary Children's Hospital, Salt Lake City, UT, USA
Background and Aims: Pediatric patients with cystic fibrosis (CF) and pediatric patients with eosinophilic esophagitis (EoE) can both present with feeding problems which can complicate clinical care. This study evaluated the association of eosinophilic esophagitis (EoE) and CF occurring in a single pediatric cystic fibrosis (CF) center.
Methods: Patients with EoE and CF from our center were identified from the electronic medical record and from the Cystic Fibrosis Foundation Patient Registry. Specific endoscopic and biopsy findings of EoE as well as clinical findings and treatment modalities were evaluated in these patients.
Results: Five patients with CF and EoE were identified (1.8% of all patients) over a 13-year time period. The average age at the time of EoE diagnosis was 5.9 years (range 1 to 16 years). Younger patients presented with feeding problems; older patients presented with dysphagia. All patients were treated with proton pump inhibitor therapy, and four patients received oral fluticasone therapy. Two patients received a gastrostomy for elemental formula therapy. Most patients had a documented history of food allergies.
Conclusions: EoE can occur in pediatric patients with CF, and the prevalence potentially may be higher than the general population. Patients with CF and associated feeding problems may need further evaluation for EoE.
33 A 34-YEAR REVIEW OF HERPES SIMPLEX ESOPHAGITIS IN CHILDREN: DOES HERPES LEAD TO EOSINOPHILIC ESOPHAGITIS OR VICE VERSA?
Julia Fritz, Mariko Suchi, Diana Lerner, Medical College of Wisconsin, Milwaukee, WI, USA
Background: Herpes simplex virus (HSV) has long been recognized as a common cause of infectious esophagitis. While the majority of cases occur in immunocompromised hosts, cases have been reported in the immunocompetent individuals. Therefore, an immunodeficiency work-up is not indicated after diagnosis of HSV esophagitis in an otherwise healthy individual. To date, 9 cases have been reported of concomitant HSV esophagitis and eosinophilic esophagitis (EoE) suggesting a causal relationship between these two entities. Most reports of HSV esophagitis in immunocompetent children are prior to publication of diagnostic guidelines for EoE and do not report follow-up endoscopies. The aim of this study is to review all patients diagnosed with HSV esophagitis at our institution and identify co-morbid conditions before and after diagnosis.
Methods: We conducted an IRB-approved retrospective review of HSV esophagitis diagnosed at a single large academic institution between 1/1982 and 3/2016. Pathology records were queried for the inclusion of “herpes” and/or “HSV”. Records including biopsies from the upper gastrointestinal tract were reviewed to identify patients diagnosed with HSV esophagitis by microscopic examination or viral culture. Medical records of these patients were retrieved for additional clinical information including presentation, treatment, and outcomes.
Results: Sixteen patients with HSV esophagitis were identified. Five cases were immunosuppressed at diagnosis. Of the 11 immunocompetent patients, 3 (27.3%) had an underlying genetic syndrome, 3 (27.3%) had no significant past medical history and no follow-up after symptom resolution. Of the 5 remaining patients (45.6%), 1 had a history of EoE prior to HSV infection. Three patients experienced symptom recurrence after initial improvement following HSV treatment and on follow-up endoscopy within 6 months of infection were diagnosed with EoE. All of these patients had co-morbid atopic conditions. One patient had symptom recurrence and a follow-up EGD showed 15–16 eos/hpf in the single obtained esophageal biopsy while on proton-pump inhibitor therapy. At last follow-up in 2003 (3 years after HSV infection), this patient continued to be symptomatic.
Conclusions: Our 34-year retrospective review supports prior studies that while immunocompromised patients are at highest risk of HSV esophagitis, this diagnosis should be considered in all patients with acute onset dysphagia/odynophagia. Among the immunocompetent patients, EoE was a frequent co-morbidity, with the majority diagnosed within 6 months of HSV infection. On biopsy specimens at the time of active HSV esophagitis, the number of eosinophils in the squamous mucosa was not high enough to suspect the diagnosis of EoE. Therefore, clinical follow-up with endoscopy may be necessary for children with atopic conditions presenting with HSV esophagitis. Further investigation is needed to clarify the relationship between EoE and HSV esophagitis.
34 NOVEL INSIGHT INTO SALMONELLA TYPHI PATHOGENESIS FROM EX-VIVO HUMAN TISSUE MODELS
Maria Fiorentin1, Alessio Fasano1, Kourtney P Nickerson1, Stefania Senger1, Marcelo Sztein2,1Massachusetts General Hospital, Charlestown, MA, USA,2University of Maryland, Baltimore, MD, USA
Introduction: Typhoid fever is a common worldwide illness, transmitted by the ingestion of food or water contaminated with the feces of an infected person, which contain the bacterium Salmonella Typhi.
The World Health Organization estimates that 22 million cases of typhoid fever occur annually, resulting in ∼200,000 deaths. In common with other enteropathogens, S. Typhi has developed means of breaching the mucosal epithelial barrier by usurping signaling mechanisms within host cells. At present, much remains to be uncovered concerning the host responses to S. Typhi infection. Available vaccines are moderately protective. Current therapeutic strategies include antibiotic treatment; however the frequency of antibiotic-resistant serovars is increasing worldwide. Additionally, in some individuals chronic S. Typhi colonization of the gall bladder culminates in gall bladder cancer, therefore highlighting the significant short- and long-term consequences of infection. Given the adverse consequences of S. Typhi infection there is a critical need to understand the mechanisms of the disease process and the host immune response for the development of efficacious and cost-effective vaccines.
Materials and Methods: Terminal ileum biopsies were collected from donors for direct infection. Whole biopsy infections were conducted using micro-snapwell mounting of tissue followed by addition of S. enterica serovar Typhi 2a to the apical surface. Prior to infection, Typhi was grown in Luria Bertoni broth under static or shaking conditions. Upon infection, changes in trans-epithelial electrical resistance (TEER), cytokine release, gene expression, and cellular localization were assessed.
Results and Conclusions: Use of whole biopsy (WB) model identified specific contributions of the epithelium in response to Typhi infection as assessed by RNA-sequencing, qPCR, and cytokine secretion. Consideration for bacterial inoculum preparation revealed that Typhi grown under static conditions express the Vi antigen, as well as, SPI-1 and SPI-2 effector proteins. Therefore, static or shaking inoculums were applied on the ex-vivo tissue model. Differences in cellular association of bacteria were assessed using immunofluorescence and transmission electron microscopy. To identify how the gut mucosa responds to infection, apical and basolateral culture supernatants were collected for cytokine production analysis. Some of the key pro-inflammatory molecules, such as IL-8 and IL-6 appeared decreased in Salmonella-infected tissues, in line with our RNA-seq data showing Salmonella-induced immune suppression. Together, our data characterizes key aspects of terminal ileum response to Typhi infection addressing a critical gap in our current understanding of Typhoid fever pathogenesis.
∗35 PROSPECTIVE STUDY FOR THE DEVELOPMENT OF A MACHINE LEARNING ALGORITHM AS A DIAGNOSTIC TOOL FOR EOSINOPHILIC ESOPHAGITIS
Mark L. Tenzer, Michael H. Hart, Kristin M. Knight, Carilion Clinic, Roanoke, VA, USA
Background: Eosinophilic esophagitis (EoE), an allergic inflammatory disease, requires expensive, repeated, and invasive esophagogastroduodenoscopies (EGDs) and esophageal biopsies for diagnosis and treatment, resulting in substantial physical, psychological, and financial impact. Previous EoE biomarker research found targets that are weakly predictive when studied independently. Using multivariate machine learning algorithms to combine biomarker and clinical data (features) into one model, we trained a support vector machine (SVM) algorithm to develop a powerful and statistically supported diagnostic tool. A previous study utilizing large retrospective and simulated datasets evaluated which machine learning algorithms and biomarkers performed best, identifying the feature set for this prospective study with a predicted specificity of approximately 0.99.
Methods: Patients presenting to pediatric gastroenterology with known or suspected EoE and planned EGDs and biopsies were enrolled. Diagnoses and survey symptomology, standard-of-care complete blood count (CBC), allergen-specific immunoglobulin E (IgE), and pathological biopsy data were collected. Eotaxin-3 and eosinophil-derived neurotoxin (EDN) levels in patients’ serum were determined through commercially available ELISAs. SVM was trained with some patients to learn to diagnose EoE, as defined by biopsy, and tested with others to assess whether the model was correct. Accuracy, sensitivity, and specificity were calculated using leave-one-out cross-validation (LOOCV): with n patients, SVM was trained with n-1 patients and tested with one patient left out. This procedure was repeated for each patient, and the results were averaged. Then, different combinations of features were temporarily removed from the model, which was re-trained, and the feature set producing the maximum LOOCV accuracy was used for the final model.
Results: Thirty patients were enrolled; seven patients undergoing treatment or missing data were excluded, resulting in a dataset of 23 patients (7 EoE, 16 control). The final model incorporated eotaxin-3 and EDN ELISAs, 18 survey questions, IgE averaged across all allergens, 15 CBC results, and 8 symptoms, with LOOCV accuracy, sensitivity, and specificity equal to 1: all patients were correctly diagnosed with only non-invasive data. Statistical significance was assessed with an approximate permutation test (n = 10,000). For accuracy, sensitivity, and specificity respectively, the approximated pvalues were 0.0000, 0.0005, and 0.0011.
Conclusions: Algorithms utilizing non-invasively obtained data successfully diagnose EoE, potentially alleviating the substantial diagnostic burden on patients and cost of care. Additional enrollment and future studies would provide further validation and refinement of the model, as well as establish a method for non-invasive, quantitative monitoring of EoE patients.
36 ESOPHAGOGASTRODUODENOSCOPY AND IMPEDANCE MONITORING IN PATIENTS UNDERGOING LARYNGOTRACHEAL RECONSTRUCTION
Terri Giordano, Joe Piccione, Karen Zur, Asim Maqbool, Albert Kim, Matthew J. Ryan, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
Introduction: Although there is controversy surrounding the use of impedance testing affecting outcomes of children undergoing laryngotracheal reconstruction (LTR), we propose routine gastroesophageal reflux disease (GERD) screening allows for treatments that significantly improve outcomes in children undergoing LTR.
Laryngoscopic findings of GE reflux include erythema, edema, nodularity, ulceration, granuloma and cobblestoning. Evidence suggests a connection between GERD and the development of subglottic stenosis, and studies in animal models has shown that gastric juices negatively effect mucosal healing after subglottic injury. We have developed a multidisciplinary aerodigestive team and any children undergoing LTR will have a preoperative diagnostic evaluation with esophagogastroduodenoscopy (EGD) and impedance testing.
This study's primary objective was to determine if the EGD and impedance testing results impact treatment decisions in patients undergoing preoperative LTR evaluation.
Methods: An observational case series with retrospective electronic medical record review was conducted at The Children's Hospital of Philadelphia analyzing existing patients’ preoperative LTR evaluation data from January 2008 through June 2014.
The primary endpoint was to determine the utility of EGD and esophageal impedance monitoring leading to changes in medical management such as adjustment of medication doses, avoidance of potential food allergens or surgical interventions prior to LTR.
Results: Seventy-four subjects were included in the study; 29 (39%) were female and 45 (61%) were male. The subjects had a median of 2.8 years. Sixty (81%) subjects had subglottic stenosis and 63 (85%) had a tracheostomy tube. Sixty-one (82%) subjects reported GERD symptoms and 7 (9%) reported none. Twenty-two (30%) had a previous fundoplication.
Of the 74 subjects, 64 (86%) on gross appearance had normal EGD results, 4 (5%) had esophagitis and 7 (9%) had gastritis. Fifty-nine patients (80%) had normal esophageal biopsies. Impedance testing revealed that 13 (18%) had an abnormal acid:non-acid ratio.
EGD and impedance study results lead to change in treatment in 24 (32%) subjects. Eighteen (75%) subjects had a new medication added. Of the 18 subjects that had a new medication added, 1 (5.6%) was prescribed an H2 blocker, 15 (83.3%) were prescribed proton pump inhibitors, 2 (11.1%) were prescribed erythromycin, 1 (5.6%) was prescribed bethanechol and 1 (5.6%) was prescribed Biaxin. Two subjects had multiple medications added. Seven (29.2%) had their current GI medication increased. One (4.2%) subject had tube feedings changed to post-pyloric feeding. No subjects had their medications discontinued.
Conclusion: Abnormal EGD and impedance results lead to a treatment change in 32% of patients in this study population. Fundoplication may not be protective in all centers and no subjects with normal EGD and/or impedance results had medications withdrawn.
37 PROTEIN-LOSING ENTEROPATHY: REDEFINING THE ANATOMY AND PATHOPHYSIOLOGY AND PROVIDING NOVEL THERAPY
Maxim Itkin, David Picolli, Yoav Dori, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Objective: To review the outcome of liver lymphatic and intestinal lymphatic embolization in patients with PLE, in whom leak of the intestinal or liver lymph was demonstrated.
Methods: This is a retrospective review of medical records and imaging of 5 consecutive patients (M/F 3/2, mean age 14. 8 y) with PLE. Three patients presented after Fontan surgery and two patients post-thoracic duct (TD) ligation for chylothorax. Lymphatic imaging included heavy weighted T2 MRI and DCMRL, intranodal lymphangiogram (IL) and liver lymphangiogram. Abnormal lymphatics were percutaneously accessed and embolized with Lipiodol or n-BCA glue.
Results: In 3 patients after Fontan surgery, liver lymphangiography demonstrated leak of liver lymph into the duodenum. Embolization of liver lymphatics with lipiodol in the first 2/3 patients was performed with temporary increase in albumin and improvement of symptoms in one patient, however complicated by duodenal bleeding. Embolization of the liver lymphatics with n-BCA in 1 patient resulted in temporary normalization of the serum albumin level and resolution of symptoms without complications. In 2 patients post-TD ligation lymphatic leak into intestine was demonstrated on DCRML and IL. Embolization of the intestinal lymphatics in these patients resulted in normalization of albumin level and resolution of the symptoms with no complications.
Conclusions: In this study, we demonstrated development of abnormal liver or intestinal flow with leakage of the lymph in duodenum in patients with PLE post Fontan surgery and TD ligations. Embolization of these abnormal lymphatics with the goal of stopping the lymph loss in intestine is a promising new treatment for this disease.
38 DELAYED DIAGNOSIS OF EOSINOPHILIC ESOPHAGITIS IN YOUNG CHILDREN
Michelle Tobin, Susan Schuval, Stony Brook Children's Hospital, Stony Brook, NY, USA
Eosinophilic esophagitis (EoE) is an emerging disorder of children and adults. Its natural history is largely unknown. Although the prevalence of this disorder is increasing, the number of patients diagnosed in early childhood remains low, and there is a paucity of clinical and epidemiologic data regarding young children with this disease. We have identified a cohort of 27 children diagnosed with EoE aged 6 years and younger. The mean age of onset of gastrointestinal symptoms was 10.9 months, with 46% of children reporting “symptoms since birth.” The most common symptoms included vomiting (63%), failure to thrive (41%), choking/gagging (33%), abdominal pain (30%) and feeding difficulty (22%). On average, these patients initially presented to the pediatric gastroenterologist at 25.9 months, at which time 67% were diagnosed with gastroesophageal reflux disease. Forty-seven percent had a known food allergy, and 37% had atopic dermatitis. Upper endoscopies (esophogastroduodenoscopy/EGD) and biopsies were performed on average at 38.5 months of age. Biopsy results revealed a mean eosinophil count of 36 eos/hpf in the mid-esophagus, and 55 eos/hpf distally. The mean interval between onset of symptoms and EoE diagnosis was 25 months. Thus, even though young children with EoE have early onset of symptoms, there still remains a significant delay before EGD, definitive diagnosis, and most importantly, the initiation of treatment. Pediatric gastroenterologists should have a high index of suspicion for EoE in young atopic children presenting with nonspecific upper gastrointestinal symptoms and should consider performing an EGD more promptly to assess for this disease.
39 FOOD IMPACTION IN PEDIATRIC PATIENTS WITH EOSINOPHILIC ESOPHAGITIS
Nicole Heinz, Samuel Nurko, Anne C Mudde, Madeleine Stout, Rina Wu, Kitzia Colliard, Eitan Rubinstein, Edda Fiebiger, Center for Motility and Functional GI Disorders, Boston Children's Hospital, Boston, MA, USA
Introduction: Eosinophilic esophagitis (EoE) is a chronic, inflammatory esophageal disease, characterized by eosinophilic inflammation and esophageal dysfunction. Upper gastrointestinal (GI) symptoms in EoE are age-dependent. Adults and adolescents typically experience dysphagia and esophageal food impaction (EFI), while the occurrence of EFI in younger children is less common and poorly investigated. There is limited information regarding the natural history of EFI in adolescents.
Objectives:1)To characterize a cohort of pediatric EoE patients who experienced EFI as the presenting symptom of the disease.
2)To describe the management of EFI patients presenting to the emergency room.
Methods: A retrospective chart review was performed of pediatric EoE patients diagnosed at 18 years or younger. Patients who presented with EFI leading to EoE diagnosis were compared to controls who did not present with dysphagia or a history of EFI, and the management of the EFIs was examined. Controls were age-matched to EFI patients at the time of EoE diagnosis. Patients with achalasia, esophageal atresia, or tracheo-esophageal fistula were excluded.
Results: 32 children with EoE that experienced EFI, and 26 age-matched controls were identified. In 81% of EFIs the impacted food was meat. Clinical characteristics are presented in Table 1, and EFI management is shown in Figure 1. Average age at EoE diagnosis in the EFI group was 13.9 ± 3.0 years (6.7–17.8 years) and was 13.5 ± 3.0 years (6.7 – 17.8 years) in the controls. 29/32 patients presenting with EFI were male vs. 13/26 controls (90.6% vs. 50%, p
= 0.001). Endoscopy results were obtained in 28/32 patients following the EFI: 42% underwent an endoscopy within 30 days post-EFI (0–252 days, mean 75.8 ± 82.9 days). No EFI patient had a stricture on endoscopy, 3 had esophageal narrowing, and 1 had a Schatzki ring.
32 patients presented with EFI. 7 passed spontaneously, and 25 presented to the ER for further management. In the ER, 7 received glucagon or nitroglycerin, 12 underwent upper endoscopy, and 6 passed without intervention. Three failed management with muscle relaxant and went on to have an upper endoscopy. 15 upper endoscopies were done in total, and 4/15 revealed no further EFI. 10/25 (40%) EFIs presenting to the ER resolved spontaneously.
• Food impaction resolved spontaneously in 40% of the children visiting the ER. This finding could have implications for the clinical management of food impaction in an emergency setting.
• Patients that present with EFI leading to an EoE diagnosis are likely to be male. Clinical characteristics of pediatric patients presenting with and without EFI are similar to previously published data in the adult population.
40 LONG-TERM CLINICAL OUTCOMES IN PEDIATRIC PATIENTS WITH EOSINOPHILIC ESOPHAGITIS
Paul Dobria1, Kiran Gorla2, Alan Schwartz1, Thirumazhisai S. Gunasekaran2, James Berman2,1University of Illinois at Chicago, Chicago, IL, USA,2Advocate Children's Hospital, Park Ridge, IL, USA
Background: Pediatric Eosinophilic Esophagitis (EoE) is a chronic, waxing and waning disease which can present with symptoms that include abdominal pain and dysphagia. A previous study demonstrated that pediatric EoE patients are at risk for adverse quality of life and long-term clinical outcomes. The Pediatric Eosinophilic Esophagitis Symptom Score v2.0 (PEESS)—a validated symptom metric—consists of items designed to measure the frequency and severity of patient- and proxy-identified EoE symptoms. Long-term outcomes of pediatric EoE have not yet been evaluated using this instrument, nor have differences between the long-term symptoms of patients with abdominal pain predominant EoE (EoE-AP) and dysphagia predominant EoE (EoE-D). Aims: Using the PEESS, 1) investigate changes in clinical outcomes of pediatric EoE over time; 2) compare the long-term outcomes of EoE-AP and EoE-D patients.
Methods: Of the 210 EoE patients contacted, 100 (48%) participated. Parent proxy-reported symptoms were collected using the PEESS. Item response theory was used to obtain measures of frequency and severity of symptoms for all 100 patients. Change in frequency and severity of symptoms over time was investigated via regression analysis. Differential item functioning (DIF) analysis was employed to compare differences in symptoms between EoE-AP and EoE-D patient groups.
Results: For the full cohort of 100 patients [mean age: 14.3 ± 5.1 years, mean time since diagnosis: 4.1 ± 2.3 years, 79% male], on average, the measure of symptom frequency decreased over time (b1 –0.145, p
= 0.035). Severity of symptoms remained stable over time (b1 0.002, p
= 0.98). 14 patients reported no symptoms. Of the 100 patients, 45 were classified as having EoE-AP, 36 as EoE-D, and 19 as other-symptom predominant. Results of the DIF analysis show that, in terms of frequency of symptoms, EoE-AP patients were more likely to report stomach pain (t –3.59, p < 0.001) and nausea (t –2.09, p
= 0.041) than EoE-D patients, who were more likely to report difficulty swallowing (t 3.13, p
= 0.003) and needing to drink a lot to help swallow food (t 2.67, p
= 0.010). On the severity scale, EoE-AP patients were more likely to report severe stomach aches (t –2.34, p
= 0.025), while EoE-D patients reported greater severity in needing to drink a lot to help swallow food (t 2.22, p
Conclusion: In this long-term follow-up study, not all EoE pediatric patients reported persistent symptoms. Across all EoE subgroups, frequency of symptoms subsided over time, while severity remained constant. Stomach pain and nausea were more prevalent in EoE-AP patients, and difficulty swallowing was more frequently reported by EoE-D patients. Stomach pain was more severe in EoE-AP patients, while the need to drink a lot to swallow was more severe in EoE-D patients. Further study is needed to better understand the impact of treatment regimens on these two clinical EoE disease phenotypes and their outcomes.
41 HELICOBACTER PYLORI ELICIT IMMUNE RESPONSE IN PEDIATRIC MONOCYTE DERIVED DENDRITIC CELLS AND T CELLS IS INDEPENDENT OF VIRULENCE FACTOR CAGA
Paul Harris, Carolina Serrano, Camila Palma, Miguel A. Leon, Macarena Vera, Caroll Hernandez, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
Background and aims: H. pylori infection in children causes increased T regulatory cell responses, which down-regulate T cell-mediated inflammation. The CagA virulence factor is the main immunodominant protein in H. pylori strains. Previous reports in mice and adults suggest a role of this oncoprotein in the suppression of DC maturation in a manner dependent of IL-10. In this study, we sought to evaluate the effect of the CagA protein from H. pylori on pediatric monocyte-derived DCs (MoDCs) and T cell response.
Methods: Mononuclear cells were isolated from peripheral blood of non-infected pediatric donors (n = 10 for DC, n = 5 for T cell studies) by gradient centrifugation. CD14+ and CD4+ naïve T cells were purified by MACS. CD14+cells were cultured for 5 days in presence of IL-4 and GM-CSF to generate pediatric MoDCs. Then we analyzed MoDC for maturation/activation markers (HLA-DR, CD86, CD83) by FACS and cytokine secretion after a 48 h exposure with H. pylori strains 26695 (western isolate), 26695 ΔCagA and Hpk5 (eastern isolate) at MOI of 10. In addition we analyzed Treg cell generation (CD4CD25Foxp3+) and cytokine secretion in 3 days DC:T cell co-culture previously stimulated with the same three strains of H. pylori for 2 hrs.
Results: H. pylori exposed MoDC, regardless of CagA status showed a suppressive phenotype characterized by low levels of expression of CD83, CD86 and HLA-DR. Moreover high levels of IL-23 and IL-10 but not IL-12 were observed in H. pylori exposed DC irrespective of CagA virulence factor. In co-culture experiments, generation of inducible Tregs (CD4CD25Foxp3+) occurred in in low percentages in response to H. pylori exposed DCs. Cytokine secretion profiles in T cells was characterized by the expression of high levels of IFN-γ and IL-10 but not IL-17 and IL-13 regardless of CagA status.
Conclusion: H. pylori induces a suppressive phenotype in pediatric MoDC with secretion of high levels of IL-10 regardless of CagA status of the strains. Further T cell differentiation from pediatric T naïve cells is also not determined by the presence of CagA and is characterized by a mixed Th1 and Treg profile.
This work was supported by Fondecyt grants #1130387 and #11140232.
42 NUTRITIONAL STATUS AND FEEDING BEHAVIORS OF CHILDREN WITH GASTROESOPHAGEAL REFLUX DISEASE OR EOSINOPHILIC ESOPHAGITIS
Pooja Mehta1, Angela M. Haas1, Nancy Creskoff Maune1, Taryn Brennan1, Michelle L. Henry1, Calies Menard-Katcher1, Shikha Sundaram1, Lucien Harthoorn2, Faith Takurukura2, Zhaoxing Pan1, Glenn T Furuta1, Dan Atkins1,1University of Colorado School of Medicine; Children's Hospital Colorado, Aurora, CO, USA,2Nutricia Advanced Medical Nutrition, Utrecht, Netherlands
Background: Gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EoE) have been associated with malnutrition and feeding dysfunction. The aim of this study was to compare the frequency of nutritional deficiencies and feeding dysfunction in children with GERD and EoE.
Methods: A prospective study enrolling children aged 1–17 with GERD or EoE was performed. Children were excluded with a dual diagnosis of GERD and EoE or other comorbidities associated with nutrition and feeding. Assessments included height, weight, 3-day food diary, and serum levels of ferritin, 25-OH vitamin D, parathyroid hormone (PTH), and prealbumin. Feeding dysfunction was characterized by the Behavioral Pediatric Feeding Assessment Scale (BPFAS), a validated measure of feeding dysfunction. It consists of measures of child behaviors as well as parental feelings and strategies used to cope with these behaviors. Comparative means and frequencies were analyzed using Student's t-tests, Chi-square, or Fisher exact tests. Spearman's rank correlation coefficient was used to determine associations with BPFAS scores. Hedges’ g was calculated to compare BPFAS scores with those of a historical group of healthy controls.
Results: Participants were divided into a nutrition cohort (GERD n = 47, EoE n = 65) and a feeding cohort (GERD n = 44, EoE n = 73) based on inclusion/exclusion criteria. The mean weight-for-length (WFL) z-score of children younger than 36.5 months of age with GERD was -1.11 and EoE was -1.12 (p
= 0.92). The BMI Z-score for children older than 36.5 months of age with GERD was 0.10 and EoE was 0.23 (p
= 0.16). Both GERD and EoE children had normal intake of calories, carbohydrates, proteins, fats, and iron but Vitamin D intake less than the daily recommended intake. Both GERD and EoE children had normal mean ferritin (30 vs. 34 ng/mL), prealbumin (21 vs. 20 mg/dL), PTH (40 vs. 38 pg/mL), and Vitamin D (30 vs. 31 ng/mL) with no significant differences between GERD and EoE groups (p
= 0.45, 0.35, 0.68, and 0.69 respectively). Thirty-two participants with EoE (49%) were on dietary elimination therapy. No significant differences in WFL z-score, BMI z-score, ferritin, prealbumin, PTH and vitamin D (p
= 0.22, 0.13, 0.20, 0.69, 0.97, and 0.64 respectively) were found when comparing children on and off dietary elimination therapy. There was no significant difference in BPFAS scores between GERD and EoE children with total BPFAS frequency scores of 81.5 for GERD and 76 for EoE (p
= 0.14) and problem scores of 8.4 for GERD and 9.7 for EoE (p
= 0.88). Both frequency and problem scores were higher than those of historical healthy controls (Hedges’g of 0.99 and 1.2 respectively).
Conclusion: A highly selected group of children with esophagitis are without nutritional complications. There may be benefit to providing anticipatory guidance to minimize mealtime challenges, monitoring for improvement, and referral to a feeding therapist if necessary.
43 STOOL CYTOMEGALOVIRUS POLYMERASE CHAIN REACTION FOR THE DIAGNOSIS OF CYTOMEGALOVIRUS CAUSING GASTROINTESTINAL DISEASE IN IMMUNOCOMPROMISED CHILDREN
Pornthep Tanpowpong, Noparat Prachasitthisak, Suporn Treepongkaruna, Chatmanee Lertudomphonwanit, Sophida Boonsathorn, Napat Angkathunyakul, Pattana Sornmayura, Wasun Chantratita, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Background: Cytomegalovirus causing gastrointestinal disease (i.e., CMV-GI disease) is a complication in immunocompromised patients which can lead to significant morbidity and mortality but can also be treatable. The current gold standard diagnostic investigation requires histopathology of mucosal biopsy demonstrating intranuclear/intracytoplasmic inclusion body. However, endoscopy and mucosal biopsy are considered invasive. Recently, studies on noninvasive markers such as stool or plasma CMV polymerase chain reaction (PCR) have been proposed to aid in the diagnosis of CMV-GI disease. Few reports on stool CMV PCR in immunocompromised adults showed promising results, and diagnostic values of plasma CMV PCR in CMV-GI disease demonstrate diverse findings. We evaluated the values of stool CMV PCR in the diagnosis of CMV-GI disease.
Objective: To determine the sensitivity, specificity and accuracy of stool CMV PCR, using histopathology as a gold standard, in the diagnosis of CMV-GI disease among immunocompromised children.
Study design: Cross-sectional diagnostic study.
Methods: We enrolled immunocompromised individuals (e.g., post-transplantation, receiving chemotherapy or high-dose corticosteroids) aged < 20 years presented with gastrointestinal symptoms (e.g., prolonged diarrhea >10 days, lower or upper GI bleeding) at a tertiary care and teaching hospital from January 2015 to March 2016. We excluded children with uncorrectable coagulopathy, suspected surgical condition, or who received ganciclovir for ≥7 days. Stool samples were analyzed for quantitative CMV PCR by Abbott Real-time amplification with the limit of detection at 20 copies per mL. All underwent esophagogastroduodenoscopy and colonoscopy with tissue biopsies to evaluate histopathology for CMV.
Results: We had performed stool CMV PCR in 31 patients but two could not undergo endoscopy. Therefore, 29 patients were analyzed. Most were female (55%) with a median age of 75 months (IQR: 33,152). Post-liver transplantation (34%) was the most common underlying condition. Prolonged diarrhea > 10 days (37%) and lower GI bleeding (34%) were two most common presenting symptoms. Two stool samples showed inhibitors and were precluded from the final analysis. Among 27 patients, we found CMV-GI disease in 7 patients (26%). The sensitivity, specificity and accuracy of stool CMV PCR were 71, 85, 82% respectively. Moreover, plasma CMV PCR was performed in all study children, which likely due to our institution's practice in immunocompromised patients. The sensitivity, specificity and accuracy of plasma CMV PCR were 100, 86, 90% respectively (by using the cutoff value of 150 copies per mL). We found a significant correlation between stool and plasma CMV PCR (p < .001).
Conclusion: Stool CMV PCR may be used as a non-invasive tool for aiding in the diagnosis of CMV-GI disease. Plasma CMV PCR demonstrates significant correlation with stool CMV PCR and represents high diagnostic values.
∗44 FOUR FOOD ELIMINATION DIET IS EFFECTIVE TREATMENT OF EOSINOPHILIC ESOPHAGITIS: A PROSPECTIVE MULTICENTER PEDIATRIC STUDY
Amir F. Kagalwalla1, Joshua B. Wechsler1, Pratibha G. Hotwagner1, Sally Schwartz1, Melanie M. Makhija1, Anthony P. Olive2, Carla M. Davis2, Seth Marcus3, Maria Manuel-Rubio1, Katie Amsden1, Kristin Johnson1, Maureen Sulkowski1, Jessica Ross1, Marion Groetch4, Mary Ellen Riffle4, Hector Melin-Aldana1, Deborah Schady5, Barry K. Wershil1, Margaret H. Collins6, Mirna Chehade4,1Ann & Robert H. Lurie Children's Hospital of Chicago and Northwestern University, Feinberg School of Medicine. John H. Stroger Hospital of Cook County, Chicago, IL, USA,2Texas Children's Hospital., Houston, TX, USA,3GI Care for Kids., Atlanta, GA, USA,4Icahn School of Medicine at Mount Sinai., NY, NY, USA,5Texas Children's Hospital., Houston, TX, USA,6Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
Background and aims: Eosinophilic esophagitis (EoE) is a chronic immune-mediated disorder of the esophagus that is triggered by food antigen. Empiric six food elimination diet (SFED) is effective in inducing remission in children and adults and is recommended diet therapy for treatment of EoE. Milk, wheat, egg and soy were the four most common food triggers identified in children treated with SFED. Our hypothesis is that four food elimination diet (4-FED) excluding milk, wheat, egg and soy should induce histological, endoscopic, and clinical remission in a majority of children with EoE.
Methods: Children meeting the consensus guidelines for diagnosis of EoE were enrolled in this prospective multicenter study and empirically eliminated milk, wheat, egg and soy from their diet and after 8 weeks underwent upper endoscopy with biopsies to establish histologic remission. Histologic remission was defined as esophageal peak eosinophil count of <15 eosinophils per high power field (eos/hpf). Secondary endpoints were identification of specific food triggers.
Results: Eighty children (68% male, 9 years, 84% white, 90% atopic) were treated with 4-FED and histologic remission was demonstrated in 51 (64%) children with decrease in esophageal eosinophil count from 61 ± 34 eos/hpf to 5 ± 4 eos/hpf (p < 0.0001) after treatment. One or more symptoms resolved in 78% of responders. Exudates improved in 96% (p < 0.0001), edema in 67%, (p < 0.0001), and furrows in 57% (p < 0.0001). Milk (85%), wheat (32%), egg (31%), and soy (17%) were triggers identified. A single food trigger was identified in 59%, two foods in 20% and three foods in 5%.
Conclusion: Empiric 4-FED by inducing remission in a majority of children with EoE is an effective dietary modality to treat EoE in children. It compares favorably with SFED.
∗45 CORRELATION BETWEEN INTESTINAL DISACCHARIDASES AND MICROBIOME IN CHILDREN WITH AUTISM
Rafail I. Kushak1, Timothy M. Buie1, Katherine F. Murray1, Stephen B. Cox2, Caleb D. Phillips2, Naomi L. Ward3, Harland S. Winter1,1Massachusetts General Hospital, Boston, MA, USA,2Research and Testing Laboratory, Lubbock, TX, USA,3University of Wyoming, Laramie, WY, USA
Autism is a neurodevelopmental disorder; however, many children with autism have gastrointestinal (GI) problems including constipation, diarrhea and abdominal pain that might affect behavior. GI problems have been associated with carbohydrate malabsorption (decreased lactase activity) or dysbiosis, alteration of the indigenous microbiota. Prior analysis of stool, colon, ileal and duodenal bacteria has revealed microbial dysbiosis, overgrowth of microorganisms, or depleted microbial diversity in autistic individuals relative to non-autistic populations.
Aims: To correlate disaccharidase activity (DA) and the duodenal mucosal microbiome of children with and without autism to determine if altering substrate availability in children with carbohydrate malabsorption affects the microbiome.
Methods: Activity of lactase, sucrase, maltase, and palatinase were evaluated in biopsies from 21 autistic subjects and 19 neurotypical subjects (controls) undergoing diagnostic upper endoscopy. Enzymes activity was evaluated using enzymatic assays. DNA was isolated from the duodenal biopsies, 16S rRNA was amplified via PCR; pyrosequencing was followed by computational analysis.
Results: There was no difference in DA between the two groups. In autistic group 17 out of 21 subjects and in controls 18 out of 19 subjects were lactase deficient. In samples from autistic subjects, the relative abundance of genus Bacteroides, Faecalibacterium, and Clostridium showed a statistically significant positive correlation with lactase activity. The duodenal microbiome in neurotypical children was different than in children with autism. None of the three groups of bacteria were observed to be correlated with disaccharidase activity in control samples, which instead showed strong positive correlations between lactase activity and the relative abundance of the genera Porphyromonas, Barnesiella, Gemella, and Leptotrichia. Correlation between activity of intestinal disaccharidases and abundance of microbiota was also found at the species level.
Conclusion: There are differences at the genus and species level in the duodenal microbiota in children with autism that could be influenced by maldigestion of lactose or nutritional differences in food consumption.
46 INCIDENCE COW'S MILK ALLERGY IN A HOSPITAL IN BUENOS AIRES
Romina Mehaudy, Marina Orsi, Claudio Parisi, Natalia Petriz, Hospital Italiano, Buenos Aires, Argentina
Introduction: The increase in food allergies in children is a worldwide concern. Studies on prevalence, incidence and the natural history of cow's milk allergy (CMA) are difficult to compare because of the deficiencies and inconsistencies in their designs. In the different series published, an incidence of 1% decreases to 0.3% when open challenges (thegold standard) are used for diagnosis. That is why it is important to determine incidence by considering all immunological mechanisms involved.
Objective: To estimate the incidence of CMA in a hospital in Buenos Aires from June 1, 2015 until January 31, 2016.
Material and Methods: A prospective study was conducted in a population of an affiliated community hospital in Buenos Aires. Data were collected using electronic medical records. CMA incidence was calculated taking into account the proportion of children with CMA detected on the annual number of births.
The diagnosis was established according to clinical practice guidelines (DRACMA).
All patients with suspected CMA underwent skin prick test, patch test and open challenges to confirm the diagnosis.
Monthly monitoring of patients was performed, recruiting those who had suspected CMA.
Results: 768 infants were included from June 1, 2015 to January 31, 2016.
Of the 768 infants analyzed in our cohort, 51% were male, and 60% were born by Caesarean section.
13 patients with clinical suspicion of CMA showed an incidence of 1.7% (95% CI, 0.9 to 3), when open challenges were performed; 8 cases were confirmed, showing a cumulative incidence of CMA of 1% (IC 95 from 0.4 to 2% CI).
Conclusion: Conducting open challenges can confirm the presumptive diagnosis of CMA.
The systematic application of this test in patients with suspected non IgE -mediated CMA can reduce overdiagnosis and improve patients’quality of life.
Although these preliminary results are similar to those seen in other countries, this is the first study done in a Latin American Country.
47 RACIAL AND GENDER DIFFERENCES IN SYMPTOMS AT PRESENTATION IN EOSINOPHILIC ESOPHAGITIS: A SYSTEMATIC REVIEW
Vincent Mukkada1, Nicholas Shaheen2, Gary Falk3, Christian Eichinger4, Helen Schofield4, Denise King4, Lora Todorova5,1University of Cincinnati College of Medicine, Cincinnati, OH, USA,2University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA,3University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA,4PharmaGenesis London, London, UK,5Shire, Zug, Switzerland
Background and Aims: Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease characterized by esophageal inflammation and dysfunction. To ensure a timely diagnosis of EoE in children, it is important for clinicians to be aware of common symptoms at presentation and potential differences across patient groups. This systematic review (SR) was designed to evaluate the literature on symptom patterns and progression of EoE in children.
Methods: Electronic databases (MEDLINE, Embase, Cochrane) and recent congresses were searched in February 2016 for studies describing the natural history of EoE in children.
Results: Of 1145 articles identified, 14 met the inclusion criteria. Data were available for 1830 patients who presented at centres in the US, Europe or Australia in 1982̈C2012. The mean age at diagnosis was 6 years. However, the average duration of symptoms prior to diagnosis was 1.2̈C3.5 yrs. The most commonly reported symptoms at presentation were dysphagia (5̈C61% of patients), emesis (17̈C60%), abdominal pain (16̈C55%) and food impaction (7̈C22%). Evidence from three studies suggests that symptoms may differ by ethnicity, age and sex. Failure to thrive (44̈C52% vs. 9̈C22%, both p < 0.05), emesis (63% vs. 37%, p
= 0.005) and emesis/acid reflux (90% vs. 52%, p < 0.01) were more common in African American (AA) than in Caucasian (Ca) children, while abdominal pain (27̈C29% vs. 40̈C57%, both p < 0.05) and food impaction (10% vs. 26%, p
= 0.003) were less common. Eczema was also more frequent in AA children than in Ca children (57̈C52% vs. 9̈C20%, both p < 0.05), while only one of two studies found asthma more common in AA compared with Ca children (51% vs. 32%, p
= 0.05). Additionally, symptom onset in AA children occurred at a younger age than in Ca children (3.7̈C5 vs. 9.1̈C10 years, p < 0.01). Food impaction, dysphagia and heartburn were associated with age ≥8 yrs, while emesis, growth failure and food refusal were associated with age <8 yrs (all p < 0.05). Food impaction was more common in males (25 vs. 11%, p
= 0.016) whereas abdominal pain was more common in females (58% vs. 35%, p < 0.001). After a mean follow-up of 7̈C15 yrs, 34̈C49% of adult patients still had difficulty swallowing. Resolution of symptoms was also rare, with the findings from one large study revealing that only 11/565 (2%) participants experienced complete resolution after a mean follow-up of 5.2 yrs. A second study found that untreated children experienced worsening of symptoms over a mean follow-up of 6 years.
Conclusions: Symptoms of EoE differ by ethnicity and age. Emesis and failure to thrive may be more common in AA than Ca children, and age at presentation may be lower in AA children. Inflammatory manifestations, such as emesis and growth failure, may be more common in younger children, while fibrotic manifestations, such as dysphagia and food impaction, may be more common in older children.
48 THE CLINICAL UTILITY OF FECAL CALPROTECTIN IN ROUTINE PAEDIATRIC PRACTICE: A REGIONAL RETROSPECTIVE COHORT STUDY
Sally Lawrence1, Aoife Casey2, David C. Wilson2, Paul Henderson2,1British Columbia Children's Hospital, Vancouver, BC, Canada,2Royal Hospital for Sick Children, Edinburgh, Scotland, UK
The clinical utility of fecal calprotectin in routine pediatric practice: a regional retrospective cohort study.
Background:Fecal calprotectin (FC) is elevated in children with inflammatory bowel disease (IBD). There is little information available regarding the use of FC in other pediatric gastrointestinal (GI) conditions.
Objectives: To determine the patient outcome of all clinical cases where FC was requested in routine pediatric practice by any pediatric specialist in a regional cohort of children. To evaluate the utility of a negative FC result when used in routine clinical pediatric practice.
Method: Using a retrospective study design, all FC samples taken over a 6-year period between 2005 and 2010 in children <17 years old were obtained. All case notes were reviewed. Patients were followed up for a minimum of 5 years. FC was measured using the PhiCal Test (Calpro). Exclusion criteria were (1) known chronic GI disease; (2) age <1yr and ≥17yrs; (3) insufficient FC sample; (4) second or subsequent FC in the same diagnostic cycle; (5) FC taken following endoscopy.
Results: 728 patients were included (62% male, median age 8.2 (IQR 4.7–11.8) years with median follow-up 7.8 (range 5.3–11.2) years). 7% (49/728) were diagnosed with IBD, 18% (131/728) had non-IBD GI inflammation, 75% (548/728) had no GI inflammation (see table for diagnostic categories). Median FC was 1110ug/g (IQR 550–1630) for patients with IBD, 110ug/g (IQR 30–360) for non-IBD GI inflammation, and 30ug/g (IQR 20–70) for no GI inflammation. 6 of 49 (12%) IBD patients had FC <200; 3 with perianal disease (minimal luminal). 1.4% (10/728) of patients with initial FC <200ug/g developed IBD in a subsequent diagnostic cycle during a follow-up period of 14–124 months. The repeat FC (n = 9) at the time of IBD diagnosis was >200ug/g in 70% (5/7); the other 2 patients had perianal disease with minimal luminal inflammation. 3.8% (28/728) of patients without a diagnosis of IBD had a FC >500ug/g; none developed IBD during follow-up but 75% (21/28) were diagnosed with non-IBD GI inflammation.
Conclusions: In routine pediatric clinical practice via a large regional cohort, FC <200ug/g rules out GI inflammation in 86% of symptomatic cases, which should help decrease endoscopy rates in this group. A minority (37%) of cases of GI inflammation are IBD, but the likelihood of IBD rapidly rises with higher FC values as FC results are higher in IBD than other causes of GI inflammation. Our study shows that an FC of >500 identifies mainly GI inflammation (non-IBD and incident IBD), but also a few cases without any evidence of GI inflammation even when followed up for a minimum of 5 years. Serial FC estimation is therefore important for patients with ongoing symptoms due to the possibility of either IBD or non-IBD GI inflammation in evolution.
49 ADRENAL INSUFFICIENCY SCREENING IN EOSINOPHILIC ESOPHAGITIS: CURRENT PRACTICE AND FUTURE IMPLICATIONS
Sanjay Kumar1, Dan Atkins2, Todd D. Nebesio1, Glenn T. Furuta2, Sandeep K. Gupta1,1Riley Hospital for Children - Indiana University Health, Indianapolis, IN, USA,2Children's Hospital Colorado- University of Colorado School of Medicine, Aurora, CO, USA
Background: Eosinophilic esophagitis (EoE) is a chronic, immune-mediated condition of the esophagus. Topical corticosteroids (TCS), mainly fluticasone propionate and budesonide, are used for treatment of EoE. Recent literature has raised concerns about the possible association between chronic TCS use and risk of adrenal insufficiency (AI), a potentially life-threatening condition.
Aim: To assess practice patterns for AI screening of EoE patients on long term TCS.
Methods: A prospective study was performed to assess the practice patterns of gastroenterologists using a self-administered online survey. An email was sent to physicians (n = 6) in various eosinophilic diseases consortia including, Consortium of Eosinophilic GI Diseases Research (CEGIR), The International Gastrointestinal Eosinophil ResearcherS (TIGERS), physician members of American Partnership For Eosinophilic Diseases (APFED) and Pediatric GI bulletin board listserv (n = 2567), with a link to an online survey. The study was IRB approved, voluntary and no remuneration was given. Study participants were divided into 2 groups based on whether they are members of different EoE consortia (C Consortia group, NC Non-consortia group). One survey was sent to an individual regardless of if they were a member of more than one consortium; i.e.,only unique surveys were analyzed. Chi-square and Student's t-test were used for statistical comparison.
Results: One hundred fifty-one respondents started the survey of which 140 completed it. Twenty-one of 140 were from C group and 119 were from NC group. Overall, 14/140 (10%) respondents screen for AI. C group was statistically more likely to screen for AI as compared to NC group [9/21(43%) vs. 5/119 (4%); P 0.0001]. The majority of respondents [10/14 (71%)] use a morning cortisol level as the initial screening test. 6/14 (43%) respondents reported abnormal initial screening in >25% of patients. Referral to endocrinologist was made if initial screen is abnormal by 43% of respondents, whereas 28% repeat the screening test and 21% perform low dose ACTH stimulation test. Overall, 9/14 (64%) respondents reported one or more confirmed cases of AI. Of those who do not currently screen for AI, 25/126 (20%) plan to screen for AI in the next 6 to 12 months, mainly due to recent literature.
Conclusions: C group members are more likely to screen for AI, possibly due to their expertise. While there is consistency in initial screening, there is considerable variability in follow-up testing. Even though an unexpectedly high number of respondents reported confirmed cases of AI, this is based on a small sample size of a selective group. However, 90% of respondents currently do not screen for AI, implying that AI may be an under-recognized condition in this patient population. Since 20% of respondents who currently do not screen report plans to change their practice pattern in next year, there is an urgent need for additional studies and formal AI evaluation guidelines for EoE patients on TCS.
50 CLINICAL SYMPTOMS AND MODIFIED BARIUM SWALLOW (MBS) SCORE IN EVALUATION OF PEDIATRIC PATIENTS WITH DYSPHAGIA AND ASPIRATION (DA)
Sarah Monks1, Peter Woodward2, Aparna Rao2, Shauna Schroeder2, Scott Schraff2, Phoenix, Lindsay Stevens2, Dana Williams2,1University of Arizona - College of Medicine Phoenix, Phoenix, AZ, USA,2Phoenix Children's Hospital, Phoenix, AZ, USA
Background: Dysphagia with aspiration (DA) is a common symptom in patients presenting for multidisciplinary gastroenterology, pulmonology, and ENT diagnostics at Phoenix Children Hospital's Aerodigestive Clinic (ADC). DA is associated with chronic respiratory or gastrointestinal symptoms, chronic thickener use, constipation, and enteral tube dependency. MBS is routinely used to evaluate dysphagia severity and guide thickener treatment of DA patients and for re-evaluation after feeding therapy or other medical and surgical intervention. Previous ADC patients with deep interarytenoid notch (DIN) given injection laryngoplasty had improved symptoms despite post-intervention MBS scores worsening, and vice versa. We initiated a Quality Improvement (QI) project to determine if MBS severity is reflective of clinical symptoms of DA, aimed at changing dysphagia monitoring protocols in DA patients.
Methods: A clinical questionnaire of DA symptoms was developed and administered over 3 months to patients aged 1–3 years who had an MBS within 6 months of their initial ADC visit, standard of care for DA. 17 symptoms (12 gastrointestinal symptoms and 5 pulmonary symptoms) were given a numerical score 0–4 based on parent recall of frequency. MBS was scored 1–10 based on the thickness of liquid recommended for aspiration prevention (1 being thin and 10 being pudding consistency). Individual symptoms and symptom sets (total questionnaire score, GI symptom score, pulmonary score) were compared to MBS scores using linear regression model.
Results: 30 families of patients aged 1–3 were surveyed with median MBS score of 6 and range from 0 to 8. 18 patients had an MBS score above 6. 23 patients had more than one MBS evaluation performed before their initial presentation to the ADC, ranging from 2 to 4 previous evaluations. Median questionnaire score was 18 (range of 4 to 53). All 30 patients presented with at least 1 GI symptom and 29 patients presented with at least 1 pulmonary symptom. 8 patients had DIN. All analysis showed NO significant correlation between individual symptom or symptom sets and MBS score, with the highest R2 value for individual symptoms being 0.05.
Conclusions: Among ADC patients with symptomatic DA, MBS severity score did not correlate with severity and specificity of symptoms, questioning the use of MBS as a repetitive tool for diagnosing severity of persistent DA and for assessing response to laryngeal cleft surgical interventions and thickener wean therapy. In our patient population the use of repetitive MBS is challenged by these findings. Our team is developing a combined clinical and radiologic tool for long-term management aimed at minimizing radiation exposure while promoting best clinical outcomes.
51 INNATE IMMUNE RESPONSES TO ROTAVIRUS VACCINES AND A RECOMBINANT ATTENUATED SALMONELLA VACCINE IN CACO-2 CELLS, IN VITRO M CELLS, AND EX VIVO HUMAN COLONIC MUCOSA
Shiuh-Bin Fang1, Ke-Chuan Wang1, Chih-Hung Huang2, Ya-Chun Lee2, Tung-Cheng Chang1, Kee-Thai Kiu1, Yan-Hao Su1, Ming-Te Huang1, Hsu-Wei Fang2,1Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan,2National Taipei University of Technology, Taipei, Taiwan
Two currently licensed rotavirus vaccines, Rotarix and RotaTeq, are efficacious and safe in protecting children from rotavirus gastroenteritis. However, innate immune responses of human intestinal epithelia to rotavirus vaccination remain little known. Furthermore, live attenuated Salmonella strains have been developed as carriers of recombinant attenuated Salmonella vaccines (RASV) expressing heterologous antigens. This study aimed to investigate innate immune responses to rotavirus vaccines and the intracellular non-replicating S. Typhimurium ΔspeG mutant comprising plasmid encoding rotavirus VP4 and VP6 as a RASV in 5-d-old Caco-2 cells, in vitro M cells by coculturing Caco-2 cells and Raji B lymphocytes, and ex vivo human colonic mucosa using surgical explants established in polarized in vitro organ culture (pIVOC). Non-polarized 4-d-old Caco-2 cells, polarized 20-d-old Caco-2 cells, and in vitro M cells were treated with Rotarix, RotaTeq, Salmonella Typhimurium ΔspeG, RASV, or none for 18 h, and human colonic mucosa ex vivo were treated with Rotarix, RotaTeq, or none for 5 h. The mRNA and protein expression levels of interleukins (IL-8 and/or IL-4, IL-6, IL-15) and hBD-2 were quantified using qRT-PCR and ELISA, respectively; the expression levels of untreated controls and treated groups were compared using the Student's t-test in cell lines and Mann-Whitney test in pIVOC. In 5-d non-polarized Caco-2 cells, Rotarix and RotaTeq significantly increased the protein and mRNA expression levels of IL-4, IL-6, IL-8, and IL-15 (all p < 0.05, Table 1), but not hBD-2, whereas ΔspeG and RASV significantly increased both expression levels of IL-4, IL-6, IL-8 and hBD-2 (all p < 0.05), but not IL-15. In 20-d polarized Caco-2 cells and in vitro M cells, the mRNA expression levels of IL-4, IL-6 and IL-8 were significantly upregulated in the Rotarix-treated Caco-2 cells, whereas those of IL-6 and IL-8 were significantly upregulated in the Rotarix-treated in vitro M cells. In addition, hBD-2 expression was non-significantly downregulated in the Rotarix-treated Caco-2 cells and in vitro M cells compared to untreated controls. RASV significantly induced higher apical secretion of hBD-2 from in vitro M cells than its vector ΔspeG. In pIVOC, Rotarix, but not RotaTeq, significantly suppressed hBD-2 mRNA expression of human colonic mucosa compared to untreated controls (1.00 [0.06–2.64] vs. 0.09 [0.05–0.19] fold change, p
= 0.041). No significant regulation of IL-6, IL-8, and IL-15 was found.
In conclusion, rotavirus vaccines can induce human innate responses in non-polarized Caco-2 cells, polarized Caco-2 cells, and in vitro M cells, particularly expression of IL-6 and IL-8. We successfully demonstrated hBD-2 suppression in ex vivo human colonic mucosa and a similar tendency in in vitro M cells after rotavirus vaccination for the first time. Our establishment of in vitro M cells and pIVOC can be developed as a platform to study novel oral vaccines.
∗52 NOVEL INSIGHT INTO SALMONELLA TYPHI PATHOGENESIS FROM HUMAN-DERIVED TERMINAL ILEUM ORGANOIDS
Stefania Senger1, Kourtney P Nickerson1, Laura Ingano1, Marcelo Sztein1, Maria Fiorentino2, Alessio Fasano1,1Massachusetts General Hospital, Charlestown, Massachusetts, USA2University of Maryland, Baltimore, MD, USA
Introduction: Salmonella enterica serovar Typhi is the causative agent of Typhoid fever, from which an estimated 22 million cases occur annually resulting in 200,000 deaths. In some areas of the globe, the incidence of Typhoid fever is as high as 500 cases out of every 100,000 children. At present, little is understood about host response to Typhi infection. As such, no long-term preventive vaccine therapy is available. Current therapeutics include antibiotic treatment, however antibiotic resistant serovars are increasing worldwide. Furthermore, chronic Typhi colonization of the gall bladder is sufficient to cause gall bladder cancer, therefore demonstrating significant health risks upon both long- and short-term infection. To design alternative therapeutic strategies, there is immediate need to understand Typhi infection and pathogenesis.
Materials and Methods. Terminal ileum biopsies were collected from donors for generation of organoid culture. Culture conditions were optimized to maintain terminal ileum epithelial stem cells; cells were then seeded onto transwell inserts for generation of monolayers. Monolayers were infected with Salmonella enterica serovar Typhi 2a to the apical surface. Upon infection, changes in trans-epithelial electrical resistance (TEER), cytokine release, gene expression, and cellular localization were assessed.
Results and Conclusions: Terminal ileum derived organoids give rise to a diversity of epithelial cells, including goblet, paneth and M cells, which are grown as a monolayer in vitro. Use of the epithelial monolayer model identified specific contributions of the epithelium in response to Typhi infection as assessed by qPCR, immunofluorescence and cytokine secretion. Differences in cellular association of bacteria were assessed using IF and TEM. To identify how epithelium responds to infection, apical and basolateral culture supernatants were collected for ELISA analysis. ELISA analysis demonstrated differences in IL-8, IL-1β and IL-12p70 cytokine production, with significant levels of basolateral cytokine secretion. Finally, infection decreased TEER at 120m post infection. Together, our data characterizes key aspects of terminal ileum response to Typhi infection addressing a critical gap in our current understanding of Typhoid fever pathogenesis.
53 LONGITUDINAL EVALUATION OF NON-INVASIVE BIOMARKERS FOR EOSINOPHILIC ESOPHAGITIS
Steve B Min1, Cade M. Nylund2, Thomas P. Baker1, Mazer Ally1, Brian Reinhardt1, Yen-Ju Chen1, Luz Nazareno1, Fouad J. Moawad1,1Walter Reed National Military Medical Center, Bethesda, MD, USA,2Uniformed Services University of Health Sciences, Bethesda, MD, USA
Background: The diagnosis and management of eosinophilic esophagitis (EoE) often requires multiple endoscopies. Serum biomarkers can be elevated in EoE patients, but their clinical utility is not well established.
Goals: To evaluate serum biomarkers in EoE subjects compared to controls and followed longitudinally in response to treatment.
Methods: We conducted a prospective cohort study of children and adults undergoing esophagogastroduodenoscopy (EGD) for suspected EoE. After completing a course of proton pump inhibitor therapy, esophageal mucosal biopsies were obtained, as well as serum analysis of absolute eosinophil count (AEC), eotaxin-3, eosinophil derived neurotoxin (EDN), eosinophil cationic protein (ECP) and interleukin-5 (IL-5). Subjects with normal endoscopic and histologic findings constituted controls. Those meeting criteria for EoE underwent repeat EGD and biomarker measurements following treatment with topical steroids for 8 weeks.
Results: AEC (263.50 cu/mm vs. 102 cu/mm, p < 0.001), ECP (26.98 ng/mL vs. 5.20 ng/mL, p < 0.001) and EDN (31.70 ng/mL vs. 14.18 ng/mL, p
= 0.004) levels were significantly elevated in EoE subjects compared to controls and correlated with esophageal eosinophilia. The level of AEC (odds ratio [OR], 1.79; 95% confidence interval [CI], 1.28–2.64) and ECP (OR, 1.61; 95% CI, 1.23–2.36) were associated with a diagnosis of EoE. Only AEC significantly predicted esophageal eosinophilia following topical steroid therapy in EoE subjects (p
Conclusion: AEC, ECP, and EDN were higher in EoE subjects compared to controls and correlated with degree of esophageal eosinophilia. Furthermore, AEC predicted post-treatment eosinophilia, suggesting a potential role in monitoring EoE disease activity.
54 COLLECTION OF STOOL ON FECAL OCCULT BLOOD CARDS IS EFFECTIVE FOR FECAL MICROBIOME BUT NOT MECONIUM MICROBIOME STUDIES IN CHILDREN
Suchitra K Hourigan, Nicole Clemency, Wendy S.W. Wong, Elisabeth Klein, Marina Provenzano, Ramaswamy Iyer, John E Niederhuber, Pediatric Specialists of Virginia, VA, USA
Background: Fecal occult blood cards (FOBC) that can be mailed and require small amounts of stool may be an effective solution for collecting fecal samples from children for large scale microbiome studies; however, the quality of sequencing resulting from this is unknown.
Aims: To compare 16 s rRNA sequencing results from stool, and also meconium, stored on a FOBC vs. in an eppendorf tube (ET) under different conditions.
Methods: 8 stool samples from children in diapers aged 1 month-2 years and 3 meconium samples were collected and stored as follows: 1) ≤2days at room temperature (RT) in an ET 2) 7 days at -80°C in an ET 3) 3–5 days at RT on a FOBC 4) 7 days at RT on a FOBC and 5) 7 days at -80°C on a FOBC. DNA was extracted and each specimen/condition was sequenced with replicates on the Illumina MiSeq. Overall microbiome structure and taxa distributions were compared between collection method. Alpha diversity (observed, Shannon, Simpson) was compared pairwise between different storage conditions. The Adonis method was used to determine whether the 5 different conditions used for storing the samples were different based on unweighted unifrac distances.
Results: Overall microbiome structure differed between individual stool specimens as expected (p < 10–5), but there was no significant difference between the storage method (p
= 0.18). However there was a significant difference between storage methods for meconium (p
= 0.039). For alpha diversity, when compared to a goal standard of stool in an ET at RT for < 2 days, there was no difference in diversity for FOBCs at 7 days at RT or 7 days at -80°C. Stool stored on FOBCs did tend to have an increase in Firmicutes and a decrease in Proteobacteria compared with ETs.
Conclusion: In stool collected from diapers from young children, there was no significant difference in alpha and beta diversity from stool collected and stored on FOBCs compared with fresh or frozen stool in ETs. There was a significant different in microbiome structure between storage conditions for meconium however. Collection of stool and mailing on fecal occult blood cards may be a low-cost.effective method for large scale population based microbiome studies in children, but not for meconium.
55 ESOPHAGITIS IN INFANTS AND TODDLERS WITH FEEDING DIFFICULTIES: PREVALENCE AND ASSOCIATED CLINICAL CHARACTERISTICS
Sara Hajizadeh Barfjani, Susanna Y. Huh, Jeffrey D. Goldsmith, Alison Cross, Elana Bern, Boston Children's Hospital, Boston, MA, USA
Background: In infants and young children with feeding difficulties, esophagogastroduodenoscopy (EGD) is increasingly performed to look for reflux or eosinophilic esophagitis, but few studies have examined the prevalence of esophagitis and associated risk factors in this population. Identification of risk factors associated with esophagitis could help physicians decide which patients should undergo EGD.
Aim: Among young children with feeding difficulties who underwent EGD, to determine the prevalence of esophagitis and compare the clinical characteristics of children with and without esophagitis.
Methods: We retrospectively reviewed electronic medical records of children who met the following inclusion criteria: initial outpatient gastroenterology visit at Boston Children's Hospital between January 2014 and December 2015 with an ICD-9 diagnostic billing code for feeding difficulties or dysphagia, and 0 to 36 months old at the time of their first EGD. We excluded subjects with pre-existing enteropathies or congenital GI anomalies. We recorded demographic and clinical data using a data abstraction form. We compared characteristics of children with and without histologic esophagitis using chi-square and t-tests.
Results: Of 171 subjects, 56% were <1 year old. Of 38 (22% of 171) subjects with histologic esophagitis, 37 had eosinophilic and 1 had neutrophilic inflammation. Gross and histologic findings were not well-correlated; 72% of subjects with esophagitis had grossly normal mucosa. Of the 22 subjects (13% of 171) with a history of food allergy, 64% had esophagitis. Food allergy history was present in 8 of 134 (6%) subjects without esophagitis, 10 of 25 (40%) subjects with <20 eosinophils/hpf, and 4 of 12 (33%) subjects with >20 eosinophils/hpf (p < 0.0001). Subjects with and without esophagitis did not differ in presenting symptom rates of gastroesophageal reflux or vomiting (63% vs. 65%, p
= 0.80), food refusal (37% vs. 41%, p
= 0.68), and choking or gagging with food (37% vs. 45%, p
= 0.36). Subjects with esophagitis had lower rates of fussiness as a presenting symptom (5% vs. 20%, p
= 0.03) but only 2 of 29 children who presented with fussiness had esophagitis. Subjects with and without esophagitis did not differ in history of past or current proton pump inhibitor (71% vs. 76%, p
= 0.57) or elemental formula use (32% vs. 19%, p
Conclusion: Almost 1 in 4 infants and toddlers under 3 years old who presented with feeding difficulties had esophagitis, usually with increased eosinophils. Among the small number of subjects with food allergy, 64% had esophagitis. These data suggest that clinicians should consider EGD to look for esophagitis in infants and toddlers with feeding difficulties and a history of food allergy.
56 PRESCHOOLERS WITH ALLERGIC DISEASES HAVE AN INCREASED RISK OF IRRITABLE BOWEL SYNDROME WHEN REACHING SCHOOL AGE
Tan Teck King, Chang-Ching Wei, An-Chyi Chen, Cheng-Li Lin, Te-Chun Shen, Tsai-Chung Li, Taiwan Society of Pediatric Gastroenterology, Hepatology and Nutrition, Taichung City, Taiwan
Objectives: To systemically investigate the risk of subsequent irritable bowel syndrome (IBS) in children with antecedent allergic diseases in a population-based case-control study in Taiwan.
Methods: We evaluated 11,242 children (age range: 7–18 years) with IBS and 44,968 age and sex-matched control subjects who had been examined between 2000 and 2008. IBS odds ratios (ORs) were calculated for children with antecedent allergic diseases, including allergic conjunctivitis (AC), allergic rhinitis (AR), asthma, atopic dermatitis (AD), urticaria, and food allergy (FA).
Results: Children with antecedent allergic diseases had a greater risk of IBS than did control subjects (p < 0.001). Among the 6 evaluated diseases, the highest adjusted OR (aOR) of 1.78 was observed with AR (95% confidence interval [CI], 1.69–1.87), and the lowest aOR of 1.40 was observed with AD (95% CI, 1.2–1.62). With 2 or more allergic diseases, the aORs increased to 2.06 (95% CI, 1.932.19) for all subjects, 2.07 (95% CI, 1.88–2.28) for girls, and 2.18 (95% CI, 2.02–2.35) for children ≥12 years old. The highest aOR of 2.94 (95% CI, 1.35–6.40) was noted when food allergy concurrent with asthma.
Conclusions: Preschoolers with a history of allergic disease had an increased risk of subsequent IBS development upon reaching school age. This risk increased in the presence of concurrent allergic disease and a higher clinical allergy burden.
57 CHARACTERIZATION OF DYSPHAGIA PREDOMINANT EOSINOPHILIC ESOPHAGITIS (EoE-D), WITH AND WITHOUT FOOD IMPACTION: 101 ADOLESCENTS
Vijayalakshmi Kory1, Vaishali Bothra1, Alan Schwartz2, Sue Weides3, James Berman3, Kiranmai Gorla3, Thirumazhisai Gunasekaran3,1Center for Childrens's Digestive Health, ParkRidge, IL, USA,2University of Illinois Hospital, Chicago, IL, USA,3 Advocate Lutheran General Children's Hospital, ParkRidge, IL, USA
EoE in children is associated with many symptoms. Consensus-2011 statement classifies patients into four groups based on predominant symptom; EoE- D, abdominal pain (AP), GERD and failure to thrive. Previously, we showed the features and outcome of EoE-D with and without food impaction (FI) in a small group of 36 patients.1 This study compares a larger group.
Aim: Compare clinical features, endoscopy+ biopsy, and outcomes of 101 EoE – D patients presenting with and without FI.
Methods: In this retrospective study, patients with EoE-D seen between January2001 and August2015 were stratified into Group I, with FI and Group II, without FI. Physical findings, CBC, esophagram, EGD+ biopsies of the duodenum, antrum, distal and mid = esophagus were captured. Diagnosis of EoE was made as per the consensus guidelines. Treatments included topical or oral steroids, dietary modification, ± PPIs, as per our EoE Clinic protocol. Symptom score for dysphagia, nausea, vomiting, regurgitation, early satiety and heartburn were scored: absent -0, mild -1, and severe-2 except dysphagia had a score up to 3 with FI. Esophageal EGD findings were scored at diagnosis and follow-up.
Results: Patients; Gr I- 30, Gr II- 71, mean age 10.9 and 10.4 yrs. (p
= 0.27). Clinical features, X-ray, EGD + biopsy findings are given in Tables 1. All patients with FI required endoscopic removal, and strictures, if present, were dilated later. Follow-up: Gr I; mean 1.7 yrs. (range 1/12–8 yrs) and in Gr II 1.1 yrs (1/12–7yrs). Treatments included; fluticasone, diet or combination, ± PPI. Symptom improvement; Gr I mean dysphagia score improved from 3 to 1.25 (p < .001) and Gr II- 1.21 to 0.71 (p < .001) and mean composite score from 3.3 to 1.45 (p < .001) and 2.49 to 1.48 (p < .001). EGD: Gr I, 15/30 (50%) and Gr II 45/71(63.4%) had a follow-up, at 8–12 weeks. Cumulative EGD score improved from 1.8 to 1.7 in Gr I (p
= .70) and from 1.6 to 1.5 in Gr II (p
= 0.08); peak eos. count in Gr. I was 53.2 at diagnosis and 37.5 after treatment (p
= .04), and in Gr. II 47.6 and 29.8 (p
= .001). Mean eos. count in Gr. I was 42 before treatment and 27.5 after (p
= .03), and in Gr. II 39.3 and 22.1 (p < .001). Patients with strictures (8); it stayed open after dilation while the small caliber esophagus was recalcitrant. 1/30 (3.3%) patients in Gr I had recurrence of FI and none in Gr II developed FI. There were no perforations.
Conclusion: There were no significant differences in the clinical features and endoscopic findings and outcome of dysphagia of the two groups. With treatment there was a significant improvement in the eosinophil count in Group II (without FI) and not in Gr I. Strictures opened up and remained open, while small caliber esophagus was recalcitrant. 1/30 (3.3%) patient in Gr I had recurrence of FI and none in Gr II developed FI. More prospective studies with long-term follow-up are needed to validate this data.
Reference:1. Gunasekaran T. Characterization of Dysphagia Associated EoE in Children with and witho
58 FACTORS ASSOCIATED WITH MORTALITY IN PEDIATRIC GASTROINTESTINAL HEMORRHAGE; A MULTICENTER DATABASE ANALYSIS
Thomas Attard1, Mikaela Miller1, Ashwath Kumar2, Chaitanya Pant2, Mike Thomson3,1Children's Mercy Hospitals & Clinics, Kansas City, MO, USA,2University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA,3Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK
Background: The risk factors associated with mortality in children with gastrointestinal hemorrhage (GIH) are poorly understood. This is presumably related to the rarity of fatal outcomes limiting the feasibility of prospective studies. GIH in children frequently complicates multisystem chronic illness. The Pediatric Health Information System (PHIS) database collects admission, diagnostic, and treatment data among 44 children's hospitals across the United States (U.S.) and affords an insight on the demographic and clinical characteristics that are associated with mortality in children with GIH.
Methods: The study is a retrospective multi-institutional database analysis. PHIS was interrogated through combined discharge diagnosis (ICD 9, ICD 10), procedure codes (CPT) and pharmacology therapeutic codes (CTC) for children diagnosed with GIH from 2011 to 2015 at the time of admission or complicating their inpatient course. Demographics, co-morbidities, inpatient course including pharmacotherapy and procedures were analyzed using the generalized linear mixed model framework. The R statistical package was used for analysis.
Results: During the period studied, 61,629 children were diagnosed with GIH through ER (43,254) 24-hour observation unit (3198), ambulatory surgery unit (257) and inpatient service (14,200). Mortality was 0.5% overall (M:F 1.1:1), mean age (SD) was 8.4 (7.4) years for mortality cases, and 6.8 (7.3) years for non-mortality cases. No difference was noted across racial definitions. Median inpatient length of stay in children with GIH who died was 18.5 days (range: 1 to 687 days), compared with 1 day for non-mortalities (range: 1 to 376 days). After adjustment for potential confounding factors, mortality was significantly associated with urban/rural residence (p
= 0.007), being higher in children reported to live in rural zip codes (OR 1.65 95% CI, 1.21–2.26), and when GIH was not reported at the time of admission compared to complicating inpatient course (OR 1.84 95% CI, 1.47–2.30,P value <0.0001). Mortality was higher in chronic liver disease (CLD) (OR 3.36 95% CI, 2.31–4.88 p < 0.0001) although chronic complex disease was present in nearly all mortality cases (97%). Treatment with proton pump inhibitor therapy (79%), H2 receptor antagonists (43%), erythromycin (9%) and octreotide/vasopressin (18%) was not ubiquitous to all mortalities; octreotide use highly associated with CLD diagnosis (χ2(1) = 2010.1, p < 0.0001).
Conclusions: This study represents the largest cohort of patients diagnosed with GIH and underscores important differences in children who succumb after the diagnosis of GIH compared to survivors. Early intervention and rapid access to specialized care appears to be important. The occurrence of GIH in children with chronic disease, especially liver disease, appears especially ominous and demands greater vigilance and greater adherence to standard pharmacologic interventions including acid suppression.
59 ESOPHAGEAL EOSINOPHILIA IN PEDIATRIC PATIENTS WITH CELIAC DISEASE RESOLVES ON A GLUTEN-FREE DIET
Wael N. Sayej, Marina L. Fernandez, Susan Goodine, Connecticut Children's Medical Center, Hartford, CT, USA
Background: Celiac disease (CD) is an autoimmune disease that has a prevalence of 1% in the general population in the United States. Esophageal eosinophilia due to gastroesophageal reflux disease (GERD) and Eosinophilic Esophagitis (EoE) have been found to be more prevalent in patients with CD than the general population, but the relationship appears to be coincidental. In this case series, we sought to characterize our patients who have CD and EoE and evaluate their response to gluten-free diet (GFD).
Methods: We searched our clinical databases for the diagnosis codes for CD and EoE and then extracted patients who had both diagnosis codes diagnosed between 2012 and2015. A total of 13 patients were identified. We then reviewed their laboratory data for positive celiac serologies and histology records to confirm the diagnosis of CD based on published diagnostic criteria (villous blunting and increased intraepithelial lymphocytes). We also reviewed the esophageal histology to confirm the diagnosis of EoE based on the 2011 NASPGHAN consensus guidelines (presence of >15 eos/hpf, basal layer hyperplasia and elongated papilla). We collected patient demographics and clinical data.
Results: A total of 13 patients were identified to have co-existent CD and EoE (ages 1–15 years, mean 8.5 years, 77% females, and 69% Caucasians, 31% with asthma). 11/13 patients were treated with GFD + PPI and 2/13 were treated with GFD only as their initial therapy. A repeat endoscopy was performed 4–9 months after the initial endoscopy. The esophageal eosinophilia resolved or improved in 9/13 (69%) patients on the GFD ± PPIs and 3/13 (23%) patients were placed on a dairy-free diet and 1/13 (8%) was placed on SFED, which eventually resolved the eosinophilia. The average peak eosinophil count on initial endoscopy was 43 eos/hpf (range 25–80), post- GFD ± PPIs was 7 eos/hpf (range 0–15) in the responders and 33 eos/hpf (range 25–40) in the non-responders. After adding dairy-free diet (n = 3) and SFED (n = 1) the peak eosinophil count decreased to an average of 2.5 eos/hpf (range 0–5).
Conclusion: We present a case series of 13 patients with CD who were found to have esophageal eosinophilia. The majority of patients (69%) responded to GFD ± PPI's, which may indicate that these patients have GERD, EoE due to wheat, or that the esophageal eosinophilia is directly related to the CD. The rest of the patients responded to other dietary eliminations (dairy, SFED), which indicates that they likely had EoE. From this series, we propose a therapeutic algorithm to manage esophageal eosinophilia in patients with CD.
60 RAPID FECAL CALPROTECTIN IN PRETERM INFANTS AT HIGH RISK FOR NECROTIZING ENTEROCOLITIS
Warapan Nakayuenyongsuk, KT Park, Megan Christofferson, Karl Sylvester, David K. Stevenson, Henry C. Lee, Stanford University School of Medicine, Palo Alto, CA, USA
Introduction: Necrotizing enterocolitis (NEC) in preterm infants of very low birth weight imposes high morbidity and mortality. Fecal calprotectin may serve as a viable non-invasive screening test to detect early signs of NEC, predicting low-grade mucosal inflammation prior to overt signs and symptoms of NEC. However, this likelihood has not been explored, as the traditional send-out ELISA calprotectin assay has limited clinical utility due to the time to result. Unlike the ELISA test, the Quantum Blue assay has a rapid turn-around of 15 minutes with the potential for point-of-care use with results possibly in advance of symptoms. As an exploratory pilot study, we aim to examine normative calprotectin values as measured by the Quantum Blue assay in a high-risk cohort.
Methods: We are conducting a longitudinal cohort analysis of patients admitted to the Lucile Packard Children's Hospital Neonatal Intensive Care Unit (NICU). The list of all infants admitted to the NICU is reviewed daily, and patients with a birth weight of <1,500 grams are enrolled. Infants with known bowel pathology are excluded from the study. Stools are collected once daily for 30 days or until postmenstrual age of 32 weeks, whichever is longer. Collected stool samples are tested using Quantum Blue® Calprotectin High Range Rapid Test. Recruitment, testing, and analysis are ongoing.
Results: Thirty-five patients have been enrolled to date. Two were excluded due to early death, leaving samples from 33 patients for data analysis. Of those 33 patients, the majority are male (n = 21, 63.6%) and were delivered via c-section (n = 26, 78.8%). Mean birth weight is 999.5 ± 307.5 g at mean gestational age 28.4 ± .7 weeks. Preliminary data show two distinct groups in our cohort: first sample in the first week of life with low calprotectin level (<200 mcg/g) versus high calprotectin level (≥200 mcg/g). Descriptive statistics show that maternal indication for preterm birth (i.e., preeclampsia or eclampsia) is significantly correlated with an elevated calprotectin level in the first week of life. Of note, history of maternal chorioamnionitis is not correlated with higher first calprotectin levels. No patient within this cohort has developed NEC, but further enrollment may prove that this subset of patients with higher initial calprotectin values may be more at risk. Additional analysis is required to determine indicators of increasing calprotectin levels after the first week of life and whether these states may be predictive of NEC.
Conclusion: In a cohort of premature, at-risk infants for NEC, there exists a subgroup of infants with high perinatal calprotectin levels in the first week of life correlating with maternal causes for preterm birth. Validation is necessary to determine whether maternal causes for preterm birth as a predictor of NEC is detectable by high calprotectin levels. A rapid calprotectin assay has the potential for point-of-care use in this population.
61 DIFFERENTIAL GASTRIC CYTOKINE RESPONSES AND LEWIS ANTIGEN MATURATION DETERMINE H. PYLORI COLONIZATION BETWEEN CHILDREN AND ADULTS: AN IN VITRO STUDY
Yao-Jong Yang1,2, Bor-Shyang Sheu1,2, Chia-Ling Lu2,1National Cheng Kung University Hospital, Tianan, Taiwan,2Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Background: The prevalence and disease severity of H. pylori infection increased from childhood to adulthood. The gastric Lewis antigens served as receptors contribute to the H. pylori colonization. Different inflammatory severity and colonization density were demonstrated on gastric epithelium between children and adults with persistent H. pylori infection. However, acute gastric cytokine responses and Lewis antigens maturations after H. pylori infection are unclear. This study aimed to validate the differences of cytokine responses, Lewis b antigen (Leb) expression, and colonization density between youth and adult primary gastric epithelium cell after H. pylori infection.
Methods: We applied a gHuman stomach fetal epithelium (HSFE) cells h and human gastric epithelial immortalized gGES]1 gcells to mimic child and adult primary gastric epithelial cells. Each group was challenged with H. pylori at various time periods. The H. pylori colonization density and Lewis antigens expression intensity were measured by flow cytometry. Cytokine expressions, including IL-6 and IL-8, were measured by ELISA.
Results: After H. pylori challenge, the colonization intensity was significantly higher in GES-1 than in HSFE cells. An earlier achieve full density of colonization in GES-1 but the colonization density slowly increased by a time-dependent manner in HSFE cells. H. pylori infection induced Lewis b antigen (Leb) expression in both GES-1 and HSFE cells. The features of Leb increment were compatible with colonization density in both cells. H. pylori-induced IL-6 and IL-8 expressions were significantly higher in HSFE cells than in GES-1 cells, respectively.
Conclusions: Leb antigen-mediated gastric H. pylori colonization is an acquisition age-dependent process. The gastric IL-6 and IL-8 responses are different between children and adults after H. pylori infection.
62 CLINICORADIOLOGICAL RISK FACTORS FOR PEDIATRIC STRANGULATED SMALL BOWEL OBSTRUCTION
YJ Chang, Chang Gung Memorial Hospital, Kwei-Shan, Taoyuan, Taiwan
Background: Diagnosing intestinal strangulation complicating a small bowel obstruction (SBO) remains a considerable challenge in children. Our goal was to evaluate the clinicoradiological parameters to predict the presence of strangulated intestine.
Methods: Medical records were reviewed for 226 pediatric patients operated for acute small bowel obstruction over a 15-year period. The clinical, radiologic findings and operation results were examined. Regression analysis was applied to identify parameters that would predict strangulated SBO.
Results: Of 226 patients with SBO, 65 patients had intestinal strangulation. In multivariable analysis, four clinical variables corrected with intestinal strangulation and were given one point each towards the clinical score: severe continuous abdominal pain, tachycardia, WBC count >14,500 /mm3, and abdominal distention. The area under the receiver operating characteristic curve was 0.77 (CI, 0.69–0.84),with the optimal cutoff of 2. With score< 2, strangulation rate was 16.5% (95% CI, 0.11–0.23) vs. 74% (95% CI, 0.59–0.85) with score ≥ 2, (p < 0.001). In patients with clinical score ≥ 2 combined with the presence of ascites on ultrasound or with the wall thickness and reduced wall contrast enhancement on abdominal computed tomography (CT) had the strong evidence of intestinal strangulation (LR 13.5, 95% CI, 0.6–0.82, p < 0.001; LR infinite, 95% CI, 0.58–0.91, p < 0.001).
Conclusions: By combining two more clinical parameter including severe continuous abdominal pain, tachycardia, leukocytosis, and abdominal distention with ascites on US or wall thickness and reduced wall contrast enhancement on CT allowed identification of strangulated SBO.
63 PREDICTIVE RISK FACTORS OF RECURRENT ILEOCOLIC INTUSSUSCEPTION AFTER SUCCESSFUL REDUCTION IN CHILDREN
Young Kim, Yim Hyung Guhn, Kwangju Christian Hospital, Gwangju, Chonnam, South Korea
Background: The intussusception recurs in approximately 10 percent of children after successful nonoperative reduction. Multiple recurrences of intussusception may occur in those with idiopathic intussusception and is not necessarily an indication for surgery.
Study Objectives: The main objective was to determine the clinical and sonographic findings that could be used to predict recurrences of ileocolic intussusceptions in children that had been successfully reduced by enema.
Methods: A retrospective search was performed on 83 children with successful enema reduction of ileocolic intussusception, 3 months to 7 years of age, during a 3.2-year period from January 2013 through April 2016. The clinical, laboratory records and sonographic findings were compared between the recurrence of intussusception group (ROI) and the non-recurrence group (NROI).
Results: Nineteen children (22.9%) of recurrence of intussusception were identified. In 16 cases of 19 ROI, and 26 of 64 NROI, the thickening of terminal ileum closest to ileocolic valve was obtained just after successful enema reduction. Statistical significances were found in terminal ileal wall thickening (median, 9.4 vs. 7.95 mm; p
= 0.0133), in contrast, not in age (median, 24.5 vs. 19.5 months; p
= 0.204), gender (male, 68.8% vs. 53.8%, p
= 0.867), irritability (median, 0.1 vs. 0.7 day; p
= 0.074), currant jelly stool (median, 0.1 vs. 0.1 day; p
= 1.0), or C-reactive protein (median, 0.69 vs. 1.83 mg/dL; p
Conclusion: Recurrence is associated with the thickening of terminal ileal wall but not clinical or laboratory findings. Given the small numbers of cases, further studies should be considered. We recommend a premeditated measurement of terminal ileal wall after successful reduction of ileocolic intussusception.
79 SMART APPS: REDUCING PRE-PROCEDURAL ANXIETY IN PEDIATRIC GASTROENTEROLOGY ENDOSCOPY PATIENTS
Anthony Anani, Lori Mahajan, Elizabeth Collyer, Katherine Lamparyk, Sarah Worley, Cleveland Clinic, Cleveland, OH, USA
Background: Anxiety is easily provoked in children undergoing invasive medical procedures including endoscopy. Two prior studies have documented the effectiveness of psychological preparation prior to endoscopy for reduction of anxiety in children. Technology now permits the common place use of hand-held devices (smart phones and tablets) as entertainment by parents and patients during medical appointments. We hypothesized that smart applications (apps) on these devices could be used as possible relaxation and distraction tools to reduce pre-procedural anxiety in children.
Objective(s): a) Compare pre-procedural anxiety in pediatric patients undergoing endoscopy within two groups: Intervention group (play with apps) vs.. control group (no apps). b) Identify areas of greatest anxiety for patients and parents during outpatient endoscopy.
Methods: Prospective randomized control study with patients between the ages of 8–18 yrs undergoing outpatient endoscopy. Patients enrolled on day of procedure and randomized into two groups intervention or control. Patients with prior endoscopy, anxiety disorder, on anxiolytics, history of cardiac/metabolic diseases, neurologically impaired/unable to complete questionnaire or who previously received psychological therapies (CBT) were excluded. Intervention group had access to an electronic tablet preloaded with smart applications- (fruit ninja, Koi pond and balloon animals) and were allowed to play with app for ≥ 10 minutes prior to procedure. Anxiety measured upon arrival and just prior to procedure;anxiety was measured with vital signs (BP, HR, and RR) and a State Trait Anxiety Inventory for Children (STAI-C). Post endoscopy questionnaire completed by patient and parents.
Results: 46 patients enrolled, with one dropout. Total of 45 patients: 22 in control group vs. 23 in intervention group. After smart app use for a minimum of ≥ 10 minutes, those in the intervention group had significantly lower mean post-intervention systolic BP (SBP) than the control group (p 0.017). There was also decrease in other surrogates of anxiety (DBP, HR and STAIC) except for RR, albeit not statistically significant. Majority of the patients and their parents in the intervention group found pre procedural use of the app beneficial (55% and 72% respectively). Post-procedure survey of patients and parents revealed IV placement and waiting for procedure as the two most common causes of pre-procedural anxiety.
Conclusions: Smart applications (apps) significantly reduced pre-procedural anxiety as measured by SBP in children undergoing endoscopy. Other surrogates for anxiety (DBP, HR, and STAI-C) also trended downward with smart app use, albeit not statistically significant. IV placement was the key driver of anxiety for patients. Parents reported waiting while child was in the procedure and observing child undergo anesthesia as major causes of anxiety for them during the procedure.
∗80 HOW OFTEN WILL CHILDREN WITH GASTROESOPHAGEAL REFLUX DOCUMENTED BY pH MONITORING STUDIES SHOW EVIDENCE OF ESOPHAGITIS?
Anupa Dalal, Anupama Chawla, Denease Francis, Stony Brook University Hospital, Stony Brook, NY, USA
Purpose: Diagnosis of gastroesophageal reflux disease (GERD) in children is challenging, as there is no defined gold standard. GERD is suspected by either the presence of acid reflux documented during esophageal pH monitoring and/or by esophagitis documented by endoscopy. There are two methods of esophageal pH monitoring including 24-hour-pH-multichannel-intraluminal-impedance measurement (pH-MII) or Bravo pH monitoring. It is unclear how often children with GERD will have both pathological reflux detected esophageal pH monitoring, and histopathological changes of mucosal injury seen on esophageal endoscopy.
Methods: We retrospectively examined clinical characteristics of pediatric patients with suspected GERD evaluated at our institution between January 2009 and July 2014. Subjects on anti-reflux medications or with known esophagitis, secondary to conditions other than GERD, were excluded.
Results: There were a total of 220 patient charts reviewed, of which 134 met inclusion criteria. All of the patients had an endoscopy and a 24–48 hour pH monitoring study. The breakdown of results and clinical features is seen in Table 1. Only a minority (24/86) of subjects with GERD had both an abnormal endoscopy and pH study, while the majority (41/86) had an abnormal pH study only. Also, we found that 21/86 only had an abnormal endoscopy, however of these subjects, 5/21 were newly diagnosed with eosinophilic esophagitis.
Impression: Children with GERD documented by Bravo/Impedance studies did not have significant changes of esophagitis detected on endoscopy. These two methods of detecting GERD are independent of each other and do not yield consistent results. Further studies must be done to establish a standard of care in diagnosing GERD.
81 COMPLICATIONS OF ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY IN PEDIATRIC PATIENTS: A SYSTEMATIC LITERATURE REVIEW AND META-ANALYSIS
Danielle Usatin, Melissa Fernandes, Isabel E. Allen, Emily R. Perito, James Ostroff, Melvin B. Heyman, University of California, San Francisco, CA, USA
Objectives: Endoscopic Retrograde Cholangiopancreatography (ERCP) is increasingly utilized in pediatrics. We hypothesize that ERCP has been applied with acceptable complication rates in children reported in the literature during the past two decades.
Methods: A systematic literature search of MEDLINE, Embase, and Web of Science from January 1995 to January 2016 was conducted for observational studies published in English. Studies reporting ERCP complications in patients <21 years of age without history of liver transplant or cholecystectomy were included. A summary estimate of the proportion of children who experienced any complications following ERCP was derived using a random effects meta-analysis.
Results: Thirty-two studies involving 2612 children and 3566 procedures were included. Subjects’ ages ranged from 3 days to 21 years. Procedures were performed for biliary (54%), pancreatic (38%), and other (8%) non-specific indications; 56% of ERCPs were interventional. Procedural complications included post-ERCP pancreatitis in166 (4.7%), bleeding in 22 (0.6%) and infections in 27 (0.8%). Pooled complication rate was 6% (95% CI, 4%- 8%). Pooled estimate of post-ERCP pancreatitis was 3% (95% CI, 2%-5%), and other complications were 1% (95% CI, 2%-5%). In the subset of articles reporting diagnostic ERCPs performed in neonates with cholestasis the pooled complication rate was 3% (95% CI, 1%-7%). Available data limited the ability to report on differences between pediatric-trained and other endoscopists.
Conclusions: Complications associated with pediatric including neonatal ERCP range widely in severity and are reported inconsistently. Our review suggests 6% of children undergoing ERCP have complications, comparable with rates reported in adults undergoing ERCP. Societal guidelines should be established for defining and reporting timing, and severity of adverse events. Further studies using systematic and standardized methodologies are needed to determine the frequency and risk factors for ERCP related complications.
82 OVER THE SCOPE CLIPS FOR TREATMENT OF ACUTE GI BLEEDING IN CHILDREN IS SAFE AND EFFECTIVE
Joshua Carroll, David M. Troendle, Nandini Channabasappa, Bradley A. Barth, University of Texas - Southwestern Medical Center, Children's Health – Children's Medical Center Dallas, Dallas, TX, USA
Introduction: Through the scope (TTS) clips have been used successfully in both adult and pediatric populations to provide mechanical tamponade in cases of gastrointestinal bleeding. Positioning and placement of the TTS clips can be challenging in certain parts of the GI tract. The safety and effectiveness of Over The Scope Clip (OTSC) in gastrointestinal bleeding has been demonstrated in adult studies; however, there are no pediatric reports demonstrating their use or effectiveness. This report is the first to detail the clinical safety and effectiveness of OTSC in the pediatric population
Methods: A bleeding registry was queried for patients where OTSC were utilized in an attempt to achieve hemostasis. Charts for these cases were then reviewed retrospectively. Data collected included age, weight, indications, rates of technical success, need for re-intervention, and complications from the procedure. All lesions were classified utilizing the Forrest classification. Technical success was defined as successful clip positioning and deployment on first attempt. Immediate hemostasis was defined as achieving hemostasis without need for utilization of other modalities during the same endoscopic session. Need for re-intervention was defined as any need for re-intervention during the follow-up period.
Results: 11 cases of OTSC utilization for hemostasis were identified in 10 unique patients and were included for analyses. Procedures were performed between 11/2014 and 5/2016. The median age at intervention was 14.7 years (range 3.9– 6.8 years). The median weight was 39 kg (range 17.4–85.8 kg). Table 1 summarizes patient and procedural characteristics. Technical success and immediate hemostasis was achieved in all cases and there were no complications. Both patients with anastomotic ulcerations required further interventions. The first (Patient 9) received additional iron infusions which were slowly spaced out following the procedure and his Hgb has remained normal with no further interventions for 163 days. The second (Patient 10) required a second endoscopy to treat additional anastomotic ulcer sites. At repeat endoscopy, the initially placed OTSC remained in place and there was no evidence of ongoing bleeding from this site. A separate site was treated during that session. This patient continues to require transfusions after her second procedure.
Conclusions: We report the first series demonstrating the safety and short-term effectiveness of the OTSC in the pediatric population for acute gastrointestinal bleeding throughout the GI tract. In our experience, it is extremely effective for non-anatomic ulcers and polypectomy bleeds even when other hemostatic techniques have failed. OTSC may be less effective in the setting of anastomotic ulcerations, reaffirming the refractory nature of this type of GI bleed although further work is needed to clarify long-term benefits.
83 TEN YEAR EXPERIENCE WITH LARGE POLYP REMOVAL (≥15
mm) IN PEDIATRIC PATIENTS
Josh Cousin1, Douglas S. Fishman1, Jose R. Rodriguez1, Surya P. Rednam1, Seth S. Septer2, Deborah Schady1,1Texas Childrens Hospital-Baylor College of Medicine, Houston, TX, USA,2Children's Mercy Hospital, Kansas City, MO, USA
Introduction: Limited pediatric data is available regarding the removal of large intestinal polyps in children. We evaluated the techniques used to remove polyps ≥15 mm in consecutive pediatric patients from 2006-2015.
Methods: We performed a retrospective single center study using a pathology database paired with endoscopic documentation software from 2001 to2015.
Polyp removal technique was divided into surgical sub-divisions (rigid anoscopy, laparoscopic, open and other) or endoscopic (snare, snare with pre-clip, snare with post-clip, snare with post-cautery, and other). Polyp type, size (with and without stalk), location and adverse events were recorded. SPSS 23 was used to calculate means, interquartile ratios and differences between groups. Institutional Review Board approval was obtained for this analysis.
Results: Of 648 polyp related procedures (585 unique patients) identified, 113 procedures yielded at least one polyp ≥15 mm from 105 unique patients. Polyp size in this group was 2.18 cm and IQR (1.68–2.5) with a maximum of 5.5 cm and 2.35 and IQR (1.7–2.5) when stalk size was included. There were 11 small intestinal polyps, 83 left-sided colon polyps, 18 right-sided polyps and one colon NOS. 20 patients had more than one large polyp removed at the same session. 86% (88 of 102) were juvenile polyps while polyposis syndromes (1 FAP, 15 JPC, 14 Peutz-Jeghers) accounted for only 26.5% of the patients. Additionally, there was one tubulovillous adenoma, but no advanced malignancies. PJS polyps were larger than JPC (p
= .036) polyps.
The mean age at time of removal was 6.5 years (range 6 months to 17 years). There was no difference between patient age and size of polyp
= (p .373). A total of 93 patients had some form of endoscopic snare cautery, standard snare (n = 72) compared to snare with other techniques (n = 21) including hemostatic clip placement, “piecemeal” or bipolar cautery. 19 patients had surgical therapy, including 10 bowel resections and 6 ligations of rectal polyps. There was a difference between size of polyps removed endoscopically vs. surgery (p
= .028). Significant adverse events (n = 4) included one equipment failure that led to repeat procedure, 2 patients had repeat endoscopies due to size or atypical location, and one patient had bradycardia that resolved with medication.
Conclusion: Large polyp removal in pediatric patients is safe and the majority are removed endoscopically with snare cautery. Surgical intervention was typically for intussusception or obstruction requiring bowel resection with polyp removal.
∗84 QUALITY INDICATORS IN PEDIATRIC COLONOSCOPY: AN AUSTRALIAN TERTIARY CENTER EXPERIENCE
Harveen K. Singh, Geoffrey D. Withers, L.C.Ee, Lady Cilento Children's Hospital, Brisbane, Queensland, Australia
Introduction: Quality indicators for colonoscopy in adults are mainly driven by colorectal cancer screening, and include cecal intubation and adenoma detection rates. Cecal intubation rates of >90% is recommended in adults by most societies and colleges internationally. In contrast, colorectal cancer is rare in children so colonoscopy is predominantly diagnostic. Common indicators for pediatric colonoscopy include investigating for inflammatory bowel disease (IBD), diarrhoea or abdominal pain. In these conditions, ileal intubation is strongly recommended as it optimizes diagnostic yield. There is, however, a paucity of data on quality indicators for pediatric colonoscopy, and it remains unclear whether high rates of cecal and ileal intubation is achievable in pediatrics.
Aims: This study was undertaken to audit all colonoscopies performed in a tertiary pediatric center to examine for the clinical indications for procedure, completion rates to cecum and ileum, and rate of significant findings.
Methods: Retrospective review of all colonoscopies from November 2011 to the end of October 2015 was performed. The ORMIS theatre management database was used to identify patients having colonoscopy using ICD-10 codes 32090 (colonoscopy) and 32087 (colonoscopy ± polypectomy). Patients having intentional flexible sigmoidoscopy were excluded from further analysis although incorrectly coded patients who proceeded to total colonoscopy were included. Patient demographics, indication for procedure, presence of trainee, quality of bowel preparation, extent of colonoscopy and confirmation of location, reasons for incomplete procedure, diagnostic findings, and complications were noted.
Results: 652 patients were identified as having had or intended to have total colonoscopy after exclusion of incorrectly coded patients. Median age of patients was 13.0 (range 0.4–18.2) years, with 53% male. The most common indications for colonoscopy were IBD review (57.9%, 378/652), rectal bleeding (10%, 68/652), abdominal pain (10%, 68/652), and diarrhea (8.6%, 56/652). All patients had procedures under general anesthesia. Trainees performed 69.8% (452/652) of procedures. Quality of bowel preparation was mentioned in 62.9% (410/652), of which 21.9% (90/410) were considered inadequate. Cecal intubation rate was 96.3% (628/652) and ileal intubation 92.4% (603/652). Photographs and/or biopsies were used to confirm extent of procedure in 99.2% of patients. Factors predicting success of ileal intubation include quality of bowel preparation and patient age. Normal histology was noted in 61.8% (403/652) of colonoscopies. 37 (5.6%) patients had polypectomy; most were juvenile polyps (54%, 20/37). No perforations occurred but three patients had hematoma, which were managed expectantly.
Conclusion: High rates (≥90%)of cecal and ileal intubation are achievable in pediatric colonoscopy. Ileal intubation should be considered a quality indicator in diagnostic colonoscopy in pediatrics.
85 RESULTS OF THE ESPGHAN ENDOSCOPY TRAINING SURVEY
Ilse Julia Broekaert1, Joerg Jahnel2, Marta Tavares3, Nicolette Moes4, Hubert van der Doef5, Christos Tzivinikos61Cologne University Children's Hospital, Faculty of Medicine, Cologne, NRW,2Medical University of Graz, Graz, Styria, Austria,3University Hospital Porto, Porto, Portugal,4University Medical Center, Antwerp, Belgium,5University Medical Center Groningen, Groningen, Netherlands,6Alder Hey Children's Hospital, Liverpool, UK
Objectives: Endoscopy training is an essential part of pediatric gastroenterology, hepatology and nutrition (PGHN) fellowship as specified in the ESPGHAN training syllabus. The aim of this study was to evaluate the endoscopy training among fellows and young professionals in PGHN. The recently published ESPGHAN syllabus suggests a minimum of 100 esophagogastroduodenoscopies (EGDs) and 50 colonoscopies for certification (D’Antiga et al., 2014).
Methods: 84 PGHN fellows participated in an electronic survey called by ESPGHAN between February 2014 and September2015. The survey comprised 32 questions on general information, number of endoscopies performed, specific endoscopic procedures, supervision and certification, and endoscopy training.
Results: Among 84 participants 28 (33%) have already finished their training and 42 (50%) are still in training. 53 fellows (63%) reported to be enrolled in an official PGHN fellowship program leading to a subspecialty certification. 32 (38%) devote their entire time to PGHN training and 34 (40%) between 50 and 99% of their time. 66 PGHN fellows (79%) are trained in endoscopy during their fellowship. Of all fellows, 29 (35%) are trained by an adult gastroenterologist and 6 (7%) by surgeons. 30 (36%) follow the ESPGHAN syllabus. Concerning the numbers of endoscopic procedures, PGHN fellows have completed 207 EGDs, 67 colonoscopies, 11 polypectomies, 10 variceal bandings and 20 PEG changes/ insertions on average. The terminal ileum is intubated in 29% most of the time (>90%). 63 fellows (75%) enjoy continuous supervision, 65 fellows (77%) keep an endoscopy logbook, and 28 (33%) have formal assessments (paper or online) during and 47 (56%) at the end of their training.
During their training 54 fellows (64%) have attended basic skills endoscopy courses and 43 fellows (51%) have completed endoscopy simulator trainings. 79 fellows (94%) wish participation in future ESPGHAN endoscopy summer schools and 75 fellows (89%) would like to attend basic endoscopy skills courses. Fellows feel that their upper GI endoscopy training will allow practicing as consultant in 86% and their colonoscopy training in 67%. 59 fellows (70%) would like ESPGHAN to be responsible for the accreditation of endoscopy centers.
Conclusions: This survey shows that endoscopy training differs among fellows in Europe regarding accomplished procedures, the training program including supervision and certification, and specific endoscopy courses. Only 36% have followed the ESPGHAN training syllabus and only 86%, respectively 67%, feel skilled enough to perform EGDs and colonoscopies when practicing as a consultant. We encourage all European GI centers to follow the ESPGHAN training syllabus to harmonize endoscopy training during PGHN fellowship throughout Europe, eventually leading to better endoscopy skills of young consultants.
86 EFFICIENCY OF MACROGOL 3350 WITH ELECTROLYTES AND ASCORBATE IN AMBULATORY PREPARATION OF COLONOSCOPY IN CHILDREN OVER 2 YEARS OF AGE
I. Irastorza1, R. Barrena2, M. Legarda3, C. Tutau3,1Hospital Universitario Cruces. UPV-EHU, Barakaldo, Basque Country, Spain,2Clínica Zorrotzaurre, Bilbao, Basque Country, Spain,3Hospital Universitario Cruces. UPV-EHU, Barakaldo, Basque Country, Spain
Introduction: Inadequate colonic cleansing is frequent in pediatric patients undergoing colonoscopy and is the main reason to admit the patient to hospital for bowel preparation. Hospital admission significantly increases the cost of the procedure and causes family discomfort. The aim of the study was to assess the effectiveness of a regime of outpatient bowel preparation with macrogol 3350 in patients older than 2 years.
Material and methods: 390 children, 2 to 14 years old (mean age 8.6 years) were given macrogol 3350 with electrolytes and ascorbate for bowel preparation the day before colonoscopy with a weight-adjusted dose of 2 g per kg. If the child failed to take the medication at home, hospital admission was arranged in order to administrate the bowel preparation by a nasogastric tube (NGT). Efficacy in colon preparation, side effects and the need for admission to complete the bowel preparation were assessed.
Results: 345 children (88%) completed the bowel preparation at home. In 295 (76%) colonic cleansing was adequate, in 44 (11%) it was incomplete but allowed us to explore the entire colon and in 5 (1%) colonic preparation was inadequate and colonoscopy was cancelled. 47 (12%) children failed to complete bowel preparation at home and were admitted to hospital (16 for vomiting and 31 for inability to drink the medication): in 26 (7%) children bowel preparation through NGT was successful, 15 (4%) children vomited the medication given by NGT and in 5 (1%) patients, NGT administration of the bowel preparation had to be stopped due to intense abdominal cramping. In total, 39 (10%) children reported cramping abdominal pain and 21 (5%) children reported vomiting. Overall, colonic cleansing at home was successful in 87% of children.
Conclusions: Outpatient bowel preparation with macrogol 3350 (2 g per kg) is successful in most cases and ensures adequate colonic cleansing resulting in a significant reduction of costs and family discomfort.
87 EXPERIENCE WITH SELF EXPANDING FULLY COVERED METAL BILIARY STENTS: CASE SERIES
Jacob Mark, Robert Kramer, Cara Mack, Children's Hospital Colorado, Aurora, CO, USA
Background: Endoscopic retrograde cholangiopancreatography (ERCP) is used for a variety of biliary and pancreatic indications in pediatric patients including biliary strictures, common bile duct stones, biliary leaks, pancreatic duct strictures and others. Biliary stent placement is often used for biliary strictures and other obstructive lesions to maintain bile flow. Multiple plastic stents are used commonly in pediatric patients but may not be effective in some cases due to migration or obstruction of the stents. Self-expanding metal stents (SEMS) have been used more recently by adult gastroenterologists, for both malignant and benign lesions but their use and placement in adolescents and children has not been well described by pediatric endoscopists. Case Presentation: We present a series of two adolescents and one young adult with complex medical needs who had biliary SEMS placed for different indications. Patient 1 is a15-year-old, 53-kg adolescent who had liver transplant for CF related liver disease and refractory post transplant anastomotic stricture that did not resolve with two rounds of multiple plastic stenting. He had improvement in bile duct diameter and GGT after 10 mm x 8 cm SEM placement (Wallflex, covered metal biliary stent, Boston Scientific, Boston, MA) for 7 weeks which was sustained at 3.5 months after placement. Patient 2 is 18-year-old, 7- kg adolescent with autoimmune hepatitis who had liver biopsy complicated by gallbladder perforation bile peritonitis. She had persistent bile leak after partial cholecystectomy, which was technically difficult because of surrounding inflammation, and did not resolve with sphincterotomy and multiple plastic stents placed across the cystic duct. Bile leak resolved with covered SEM placement 8 mm x 8 cm across the cystic duct for 6 weeks and she has had no symptoms of bile leak recurrence 4 months after last stent removed. Patient 3 is a 24-year-old, 36-kg young woman with Rett syndrome and multiple pulmonary and neurologic comorbidities who had obstructive choledocholithiasis 2 years after cholecystectomy. She continued to have multiple biliary stones and signs of obstructive choledocholithiasis after multiple ERCPs with balloon sweeps, sphincterotomy and multiple plastic stenting so 10 mm 6.0 cm SEM was placed with resolution of biliary obstruction after 8 weeks. In all cases, the stents were well tolerated and no adverse events were encountered. Removal was performed endoscopically using a raptor forcep (US Endoscopy, Mentor, OH) without difficulty.
Conclusion: SEMs may be considered by pediatric endoscopists for patients with benign obstructive lesions or perforations of the common bile duct who are not responding to plastic stents. Additional research is needed, however, for more comprehensive evaluation of the efficacy and potential adverse events in pediatric patients undergoing SEM therapy.
88 SAFETY AND EFFICACY OF THE ADVANCEMENT (PUSH) TECHNIQUE IN THE TREATMENT OF ESOPHAGEAL FOOD IMPACTION IN CHILDREN
Jamal Kriem, Riad Rahhal, University of Iowa, Iowa City, IO, USA
Background: Esophageal food impaction is one of the conditions that often requires immediate attention including urgent endoscopy. Adult- based guidelines support the use of the extraction (pull) technique but allow the consideration of the advancement (push) technique with caution due to the high probability of esophageal pathology and risk of perforation. The NASPGHAN guidelines mention the use of gentle advancement for disimpaction but elaborate that the use of this technique in children has not been studied.
Hypothesis: The push technique is safe and effective in the treatment of pediatric esophageal food impactions.
Methods: This was a retrospective cohort study of all pediatric patients presenting with esophageal food impactions to a pediatric tertiary care center from 2003 to 2016. Procedures were identified using billing records.
Results: Two hundred and forty-two procedures were identified based billing codes for esophageal foreign body removal. Forty procedures were for treatment of esophageal food impaction in a total of 24 patients (range: 1–4 procedures per patient). The most common underlying diagnoses were eosinophilic esophagitis (42%) and history of tracheoesophageal fistula (38%). The cohort had a median age of 8.5 years and median weight of 35.2 kg. Initial endoscopic disimpaction methods include 21 push technique and 19 pull technique attempts with success rates of 62% and 68% respectively (p
= 0.67). Unsuccessful attempts using one technique were successfully accomplished using the other technique. All patients were discharged within 24 hours of the procedure, except for one patient who was transferred from another hospital with an esophageal perforation secondary to a failed disimpaction. The perforation was managed conservatively. No procedure-related complications were reported at our center. The two groups of patients (managed by the two disimpaction techniques) did not differ in age, weight, gender, presenting symptoms, type of anesthesia used or underlying diagnoses except that patients with known fixed esophageal strictures (n = 4) were managed using the pull technique only.
Conclusion: This study shows that the push technique is as safe and effective as the pull technique in managing esophageal food impactions in pediatric patients in the absence of known fixed esophageal strictures.
89 THE IMPACT OF AN INTERACTIVE COMPUTER APPLICATION ON THE QUALITY OF COLONOSCOPY PREPARATION, PATIENT SATISFACTION AND OUTPATIENT AMBULATORY CENTER EFFICIENCY
James Brief, Anupama Chawla, Jeffrey Morganstern, Stony Brook Children's Hospital, Stony Brook, NY, USA
Background: Colonoscopies can be a source of anxiety for patients and their families. From a grant provided by NASPGHAN, we developed software (an “app”) that familiarizes patients with the procedure, answers commonly-asked questions, informs patients of when and where to report for their colonoscopy and guides patients through the colonoscopy prep process, providing real-time instructions about which medications to take, when to take them and how they should be prepared.
Methods: 46 patients aged 5–18 were randomized to receive either written or software prep instructions. Prep quality was measured with the Boston Scoring Scale. The number of calls to the gastroenterology service were recorded. Patient arrival time was recorded on the day of their procedure. A questionnaire was given to patients on the day of the colonoscopy.
Results: App users had superior mean Boston scores of 9.80 versus controls’ 7.96 (p
= 0.014). Although not statistically significant, 10/20 (50%) app users had improved knowledge of the colonoscopy versus 8/22 (36.4%) controls (p
= 0.37). App users made fewer phone calls to the GI service than controls (6 vs. 2), although this difference also did not reach statistical significance (p
= 0.27). There was no difference between arrival times at the endoscopy suite between app users and controls (p
Conclusion: App users had significantly better quality preps than control subjects. While results showed a trend towards app patients feeling better informed and knowledgeable about the colonoscopy prep, and requiring less physician guidance, these results were not statistically significant. App and control subjects arrived at the endoscopy suite at nearly the same time. We anticipate that future studies with greater numbers of subjects will reach statistical significance for these measures.
90 SAFETY AND EFFICACY OF ENDOSCOPIC ASSISTED PUSH GASTROSTOMY USING GASTROPEXY TECHNIQUE COMPARED TO PERCUTANEOUS GASTROSTOMY TUBE PLACEMENT
Javier Monagas, Lauren Del Bosque, James Noel, R. Adam Noel, Baylor College of Medicine, San Antonio, Texas, USA
Background: Most pediatric gastroenterologists use the pull technique for percutaneous endoscopic gastrostomy tube placement (PEG). Gastropexy is a new technique for endoscopic gastrostomy tube placement. T-fasteners are placed through the skin into the stomach, attaching the stomach to the abdominal wall, visualized directly by endoscopy. Serial dilators are used to create a gastrostomy tract, allowing a low profile gastrostomy (GT) or gastrojejunostomy tube (GJT) to be placed. There are no published studies that compare the gastropexy procedure outcomes to the standard PEG procedure in pediatrics.
Objective: To study the safety and outcomes following gastropexy vs. PEG.
Methods: Gastropexy and PEG patient charts were compared for immediate complications(perforation, bleeding, and infection), pain and long term complications (feeding problems, pain, tube dislodgement, infection, bleeding, granulation, readmission, and death) in the three months following procedure.
Inclusion criteria: Pediatric patients requiring gastrostomy placement for enteral nutrition. Subjects were from 0–17 years of age that underwent a procedure in 2014 to 2015.
Results: 13 subjects who underwent gastropexy were between the ages of 1–16 years (avg. 6.6 years), 6 males, with average weight of 23 kg. Fourteen subjects who underwent PEG placement ranged from 0.16–9.5 years of age (avg. 1.5 years), 7 males, with average weight 7.2 kg. There were no immediate short-term complications in either group. Long-term complications were assigned a score according to the severity values, ranging from 0 to 7. The average complication score for both groups was 3, with a median and mode of 2. The procedure length averaged 26 minutes (min) in the gastropexy group compared to 10 min in the PEG group. Average anesthesia time was similar- 53 min in gastropexy group versus 47 min in PEG. Pain treatment for mild, moderate and severe pain was similar in both groups except Toradol that was only used by the gastropexy group. Pain treatment was shorter in the gastropexy group (avg. 1.7 days) vs. PEG group (avg. 3.5 days). Time to start clears was <24 hours in 11/12 subjects for the gastropexy group and in 10/11 subjects for the PEG group. Time to start feeds was <36 hours in 8/11 subjects for the gastropexy group and 12/14 subjects for the PEG group.
Discussion: Our results show that the gastropexy technique is a safe and effective alternative for placement of GT and GJT. The major advantage is that patients who underwent gastropexy did not require a second procedure compared to PEG patients for low profile tube conversion or subsequent placement of a GJT. Disadvantages include longer procedure time for the gastropexy group likely due to the learning curve and differences between operators, but the last 5 procedures averaged 17 minutes.
91 ESOPHAGEAL ENDOSCOPIC DILATION IN CHILDREN: EXPERIENCE OF A TUNISIAN PEDIATRIC ENDOSCOPY UNIT
Siala Nadia, Jeridi Yasmine, Mohamed Lamouchi, Ouerda Hayfa, Azzabi Ons, Maherzi Ahmed, Mongi Slim Hospital, Sidi Daoud, La Marsa, Tunisia
Background: The endoscopic treatment of esophageal stenosis seems to be the most frequently used strategy in children. Improvement in endoscopes and techniques have led to the increase in the number of patients who are conservatively treated with endoscopic dilation rather than surgical treatment. This is a report of our experience with esophageal dilation, its indications, methods and results in children.
Methods: Retrospective study of children admitted in our pediatric endoscopy unit for esophageal dilation between November 2007 and March 2016.
Resuts: 39 admissions were registered. There were 24 males and 15 females with a mean age of 4 years. Esophageal atresia anastomotic stenosis (n = 2, 25.6%) and post-corrosive esophagitis(n = 0, 25.6%) are the most frequent types of cicatricial esophageal stenosis. The other indications were peptic stenosis (n = , 15.3%), achalasia (n = ,12,82%), congenital stenosis(n = , 7.6%), herpetic esophagitis (n = , 2.5%) and unidentified causes (n = 2, 5.1%). The average number of sessions to achieve adequate dilation was 4 per patient with extremes from 1 to 13. Different dilators were used: in 86 cases (54%) we used the balloon dilators, whereas in 37 (23.2%), the Savary-Giliard bougie. Balloon followed by Savary-Giliard bougie dilation had been used in 25 cases (15.7%). In 11 sessions, the dilation method had not been mentioned. Dilation was successful in all cases except one.
Conclusion: The conservative treatment of esophageal stenosis rather than surgery is a well-known strategy for children. Young patients can be treated effectively and safely only by endoscopic dilation.
92 RELIABILITY ASSESSMENT OF ENDOSCOPIC DISEASE SEVERITY USING CENTRAL VIDEO REVIEW OF COLONOSCOPIES IN PAEDIATRIC PATIENTS WITH CROHN'S DISEASE: DATA FROM THE CANADIAN CHILDREN INFLAMMATORY BOWEL DISEASE NETWORK.
Nicholas Carman1, Peter Church1, Hien Huynh2, Thomas Walters1,1The Hospital for Sick Children, Toronto, ON, Canada,2University of Alberta, Edmonton, AB, Canada
Objectives: Reliable and consistent endoscopic assessment of mucosal disease severity is important in the evaluation of patients with inflammatory bowel disease (IBD). There are a number of scoring tools available for use in the endoscopic assessment of Crohn's disease, however none have been formally evaluated in pediatric patients. To reduce variability in the assessment of endoscopic severity, centralised review of video colonoscopies has been increasingly implemented in adult clinical trials, where excellent inter-rater reliability has been noted in the hands of IBD experts. To date, similar assessments have not been performed in pediatric IBD. We undertook to assess inter-rater reliability for the Simple Endoscopic Score (SES-CD) and Crohn's disease Endoscopic index of Severity (CDEIS), using videos of colonoscopies performed in pediatric patients from the Canadian Children IBD Network.
Methods: Video recordings of colonoscopies obtained from pediatric patients with Crohn's disease undergoing endoscopic assessment at Network sites were utilised for the analysis. 3 central readers reviewed the videos independently, and were blinded to clinical information. Colonoscopies were assessed using data encompassing the commonly employed scoring tools for Crohn's disease (SES-CD and CDEIS), assessing the total score and individual items across each anatomical segment. A global assessment of endoscopic lesion severity (GELS) was also recorded using a visual analogue scale. Inter-rater agreement was measured using Intraclass correlation coefficients (ICCs) with 95% confidence intervals. Correlation between scoring tools was measured using Pearson's test of correlation (r).
Results: The ICC for inter-rater reliability for SES-CD was 0.94 (95% CI, 0.84–0.98), for CDEIS was 0.83 (95% CI, 0.58–0.93), and for GELS was 0.90 (95% CI, 0.74–0.96). There was very good correlation between the SES-CD score and CDEIS (r 0.81, p < 0.001). The correlation between GELS and each scoring tool was also very good, with SES-CD and CDEIS demonstrating r 0.77 (p < 0.001) and r 0.81 (p < 0.001) respectively. The most common sources of disagreement between readers were estimation of the degree of ulcerated surface and evaluation of the depth of ulceration. Disagreement was most notable in the transverse colon (ICC 0.48 and 0.46 for ulcer surface and ulcer depth respectively).
Conclusion: Centralized video review of colonoscopy is a feasible way to assess endoscopic severity in pediatric Crohn's disease. Assessment of the existing scoring tools (SES-CD and CDEIS) using video recordings showed excellent inter-rater reliability in the hands of IBD physicians familiar with the tools. These scores also correlated well with GELS, demonstrating some measure of validity for these tools in pediatric Crohn's disease. Ongoing assessments are planned in order to explore the variability in scoring and relationship to GELS across different disease phenotypes.
93 DIAGNOSTIC YIELD OF ESOPHAGOGASTRODUODENOSCOPY IN CHILDREN PRESENTING WITH FAILURE TO THRIVE AND FEEDING DISORDER
Rachel Dunn, Alex Boomgarden, Katherine Larson-Nath, Praveen Goday, Children's Hospital of Wisconsin, Milwaukee, WI, USA
Background: Esophagogastroduodenoscopy (EGD) is commonly performed in infants and children with failure to thrive (FTT) or feeding disorder (FD). There have been no studies looking at the efficacy of performing EGDs in these populations.
Aim: To determine the diagnostic yield of EGD in children diagnosed with FTT or FD and to document the association between the presence of FTT, FD, other presenting symptoms, and key past medical history and family history with pathological findings on endoscopy.
Methods: We performed a retrospective cross-sectional cohort study in children <5 years of age who were undergoing EGD for evaluation of FTT or FD at the Children's Hospital of Wisconsin between December 2010 and June 2014. We documented symptoms present prior to EGD including history of atopy, food allergies, family history of atopy/food allergies, specific progression of feeding skills, and family history of eosinophilic esophagitis. We also looked at the association between the presence of FTT, FD, and other symptoms, and pathological findings on endoscopy.
Results: A total of 350 children met criteria for the study. Their mean age at time of EGD was 2.12 years (SD 1.247). The mean z-scores for weight, weight-for-length z-score (<2 y) and BMI Z-score (>2 y) were -0.97 (SD 1.466), -0.59 (SD 1.442) and -0.47 (SD 1.406) respectively. Ninety-eight children (28%) had FTT alone, 160 children (45.7%) had FD alone, while 90 children (25.7%) had both FTT and FD. EGDs were diagnostic in 40.8% of FTT alone, 25.6% FDD alone, and 38.9% FTT and FD combined. In the entire cohort, the diagnostic yield of EGD was 33.1%. The top diagnoses revealed by the EGD in FTT alone were abnormal pancreatic stimulation test (ABST) in 10.2%, celiac disease 8.2%, and eosinophilic esophagitis 5.1%. Other important diagnoses in this subgroup included H. pylori infection 2%, autoimmune enteropathy 1%, IPEX 1%, and antral web 1%. The top diagnoses in FD alone were reflux esophagitis 10.6%, eosinophilic esophagitis 6.9%, and ABST 1.3%. The top diagnoses in children with both FTT and FD were reflux esophagitis 13.3%, eosinophilic esophagitis 8.9%, and ABST 5.6%.
Chi square analysis showed that the presence of diarrhea and food allergies increased the diagnostic yield. EGDs were diagnostic when diarrhea was a presenting symptom in 50.9% vs. 30.3% in the absence of diarrhea (p
= 0.003) and food allergies occurred in 35.4% of diagnostic EGDs vs. 25.4% of non-diagnostic EGDs (p
= 0.023). Other historical features were not associated with significant differences in diagnostic yield.
Conclusions: There appears to be benefit in using EGDs in the evaluation of FTT and FD. The presence of diarrhea or food allergies may be associated with increased diagnostic yield.
94 AN INNOVATIVE APPROACH: IMPLEMENTATION OF AN ASYNCHRONOUS PILOT PEDIATRIC GASTROENTEROLOGY E-CONSULT PROGRAM
Rajitha D Venkatesh1, Sandhya K. Rao2, Timothy G. Ferris2, Jason H. Wasfy2,1MassGeneral Hospital for Children, Boston, MA, USA,2Massachusetts General Hospital, Boston, MA, USA
Electronic consultation (e-consults) have emerged as a promising approach to enhance provider communication and have demonstrated feasibility and facilitated timely specialty advice in a variety of settings. E-consults are alternatives to traditional outpatient pediatric gastroenterology visits in which a patient physically presents to the office for an in-person visit. In the adult literature, studies have demonstrated that e-consults provide responsive high-quality care, reduce total costs of care as well as high rates of satisfaction among both providers and patients. Nevertheless, information about e-consults in pediatrics is limited. We sought to establish an e-consult program in pediatric gastroenterology and assess preliminary results. At Mass General Hospital for Children (MGHfC), a tertiary pediatric center, e-consults in outpatient pediatric gastroenterology enable primary care providers (PCP) to submit patient-specific clinical questions to a specialist. At MGHfC, a tertiary pediatric center, e-consults in outpatient pediatric gastroenterology enable PCP's to submit patient-specific clinical questions to a specialist. MGHfC is part of the Partners Healthcare network, an integrated healthcare network and is part of several accountable care organization (ACO) contracts with a shared electronic medical record system. Structured e-consults are sent to a pediatric gastroenterologist who reviews the electronic data and imaging as appropriate and then provides detailed clinical recommendations to the referring doctor. The pediatric gastroenterologist is reimbursed a flat fee through the ACO. To assess the results of this pilot project, medical records were individually reviewed by a pediatrician. From July 2015 to November 2015 we implemented e-consult referrals by MGHfC PCPs. PCPs received recommendations within 48 hours of their referral request. The patients referred for e-consult ranged from 2 months to 5 years of age. The reasons for referral included abdominal pain, reflux, poor weight gain, abnormal liver function tests and acholic stools. Recommendations included reassurance, indications for further testing as well as medication and formula changes. Only one was referred for a traditional consult. No clinical adverse events related to the e-consult were detected. Although we currently have limited roll-out in our pilot, we anticipate being able to report on over 60 e-consults by October 2016. Even with our initial implementation, we were able to demonstrate feasibility of a pediatric gastroenterology e-consult pilot program within a large ACO. An e-consult program allows efficient, high-quality recommendations to PCPs for a variety of referral questions. This potentially results in significant cost savings by avoiding a traditional in-person visit. As a pilot study, our next steps aim to expand this to other pediatric subspecialties as well as look at provider satisfaction and cost analysis of our program.
∗95 CARBON DIOXIDE INSUFFLATION VERSUS AIR INSUFFLATION FOR COLONOSCOPY IN DEEPLY SEDATED PEDIATRIC PATIENTS: A PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, CONTROLLED TRIAL
Rajmohan Dharmaraj1, Rachel Dunn2, Julia Fritz1, Mahua Dasgupta1, Pippa Simpson1, Jose Cabrera1, Adrian Miranda1, Diana Lerner1,1Medical College of Wisconsin, Milwaukee, WI, USA,2 Children's Hospital of Wisconsin, Milwaukee, WI, USA
Background and Aims: Several studies in adults have reported reduced abdominal pain after colonoscopy with carbon dioxide (CO2) insufflation in lightly sedated and deeply sedated patients. This study was designed to investigate the efficacy and safety of CO2 insufflation in deeply sedated children undergoing colonoscopy.
Methods: This was a prospective, randomized, double-blind clinical trial. We recruited 100 consecutive pediatric patients who underwent colonoscopy for various indications. Patients were randomly assigned to either CO2 or air insufflation. Deep sedation was achieved with a combination of propofol, sevoflurane and nitrous oxide. Post-interventional pain levels were registered on a 10-point visual analog rating scale. Abdominal circumferences and end tidal CO2 (ETCO2) levels were measured. Complications during and after the procedure were recorded.
Results: There were no significant differences in pain scores between the two groups at immediately, 1 hour, 2 hours, 3 hours, 4 hours, at discharge, 24 hours and 72 hours after colonoscopy. We performed a subgroup analysis on patients with chronic abdominal pain undergoing colonoscopy and found no statistically significant difference in pain scores between air and CO2 insufflation in this patient population. We also analyzed the factors related to pain scores and found that duration of the procedure was significantly associated with pain immediately after the procedure (p
= 0.01) and previous abdominal surgery significantly associated with pain at discharge (p
= 0.02). The mean highest ETCO2 values measured during the procedure was statistically different, being higher in the CO2 group than in the air group (CO2: 54.4 ± 8.21 Hg vs. air: 48.9 ± 6.36 Hg, p
= 0.0003). No clinical signs of impaired ventilation or other adverse events were observed. The mean increase in abdominal circumference was greater with air than with CO2, however, this was not statistically significant (air: + 1.32 cm vs. CO2 - 1.26 cm, p
= 0.17). The procedure times including time to cecum and duration of colonoscopy, and time to discharge after the procedure were not statistically different between the two groups [time to cecum (min) air 12.8 ± 7.3 vs. CO2 12.9 ± 7.8, p
= 0.89; duration of colonoscopy (min) air 28.1 ± 13.6 vs. CO2 28.8 ± 14.4, p
= 0.9; time to discharge after the procedure (min) air 137.2 ± 35.6 vs.. CO2 126.6 ± 37.4, p
= 0.06]. We didn’t observe any statistically significant difference between the two groups in pain medications received and adverse events during recovery, and post-procedural events following discharge.
Conclusions: CO2 insufflation during colonoscopy may not of benefit in reducing the post-procedural abdominal pain associated with the procedure. Duration of the procedure and previous abdominal surgery were identified as key predictors of pain after colonoscopy.
96 OUTCOME OF BAND LIGATION IN ESOPHAGEAL VARICES OF BANGLADESHI CHILDREN: A TERTIARY CENTRE EXPERIENCE
Salahuddin Mahmud1, Syed Shafi Ahmed1, Jahida Gulshan2, Farhana Tasneem3, Bazlul Karim4,1Dhaka Shishu (Children) Hospital, Dhaka, Bangladesh,2Institution of Statistical Research and Training, University of Dhaka (DU), Dhaka, Bangladesh,3Institute of Child Health, Dhaka, Bangladesh,4Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh
Background: Band ligation is the main endoscopic treatment for esophageal varices. In our country, few studies are available in adults, and none are available absent in children.
Objective: To see the outcome of band ligation of esophageal varices in extra-hepatic and hepatic cases of portal hypertension.
Materials andMethods: The prospective study was done in the Department of Pediatric Gastroenterology, Hepatology & Nutrition, Dhaka Shishu (Children) Hospital, Dhaka, Bangladesh on 40 consecutive cases of portal hypertension enrolled from April 2014 to March 2016. Every case was treated with band ligation followed by Tab. Propranolol. Cases were followed up for a minimum period of one year after the band ligation.
Results: Age of the children was 2–12 years with mean age of 7.2 ± 4.3 years and male:female ratio was 1.5:1. Out of 40 children, 32 (80%) were extra-hepatic and 8 (20%) hepatic (chronic liver disease with portal hypertension) causes. Only 1 session required in 50% extra-hepatic cases and multiple (2–3) sessions required in hepatic (100%) cases. Almost same number of band (average 2–3) required in every session of both cases. Grade-II esophageal varices with red sign were more common in extra-hepatic cases and severity of grading much more (grade-III and IV) in hepatic cases. Gastric varices were more common in hepatic (50%) cases than extra-hepatic (12.5%) cases. Recurrence of bleeding occurred in all hepatic (100%) cases and half (50%) of the extra-hepatic cases. Early re-bleeding was more common in hepatic (75%) cases and late re-bleeding in extra-hepatic cases (87.5%). Minimal side effect like discomfort (25%) and Nausea (25%) were present after the procedure.
Conclusion: Extra-hepatic was the most common etiology of portal hypertension in studied children. Fewer sessions were required in extra-hepatic cases than in hepatic cases. Severity of grading, re-bleeding and associated gastric varices were more common in hepatic cases. Band ligation is the treatment of choice for the control of acute variceal bleeding and prevention of re-bleeding with less complications.
97 OUTCOME OF CHILDREN AFTER SURGICAL REPAIR FOR ESOPHAGEAL ATRESIA: A TUNISIAN COHORT
Samir Boukthir, Ahmed Meziou, Ines Brini, Sonia Mazigh Mrad, Khedija Bousetta, Mourad Hamzaoui, Said Jlidi,
Azza Sammoud, Hôpital d’Enfants – Bab Saadoun, Tunis, Tunisia
Aim: To determine the frequency of gastrointestinal and respiratory complications after surgical repair for esophageal atresia.
Methods: A retrospective analysis of the endoscopic files during the last 12 years (from January 2003 to December 2015) revealed that 41 children presenting with esophageal atresia, 23 males and 18 females, mean age 2.8 years (± 3.3), underwent upper gastrointestinal (UGI) endoscopy for dysphagia (n = 16, 39.1%), cyanosis (n = 3, 7.3%), abdominal pain (n 2, 4.8%), food impactions (n = 1, 2.4%), UGI bleeding (n = 1, 2.4%) and miscellaneous causes (nn18, 44%). Study parameters included dysphagia, gastroesophageal reflux disease, anastomotic stricture, asthma, recurrent respiratory infections.
Results: The mean follow-up was 4.3 years (± 1.8). Thirty four children had a type 3 atresia (82.9%) and 7 (17%) had associated congenital malformations (musculoskeletal 3, renal 2, digestive 2). A primay repair was performed in 34 cases (82.3%) with anastomotic tension for 5 of them. Thirty patients (73.1%) had gastrointestinal disorders: gastroesphageal reflux (n = 2, 29.2%), anastomotic strictures requiring endoscopic dilatations (n = 28; 68.3%), feeding troubles (n = 3), food impaction (n = 1). Ten children (24.4%) had respiratory complications: asthma (8), recurrent respiratory infections (2).
Conclusion: Morbidity of esophageal atresia after surgical treatment is very high with a high frequency of gastrointestinal complications in this cohort. We recommend an extended specialized follow-up of this population.
98 AMOXICILLIN CLAVULANATE DOES NOT IMPROVE COMPLETION RATE OF CAPSULE ENDOSCOPY IN PATIENTS UNDERGOING ENDOSCOPIC PLACEMENT
Sonal R. Patel, Lee M. Bass, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
Background: Capsule endoscopy (CE) in pediatrics can be challenging due to difficulty swallowing the capsule, requiring endoscopic placement. Completion of CE is suboptimal with completion rates of less than 85%. Endoscopic placement has been noted to be a risk factor for incomplete CE studies. Previous studies using prokinetic medications in orally ingested CE have not demonstrated consistent results in improving CE completion rates. Amoxicillin-clavulanate is noted to stimulate small intestinal motility in certain patients. We aim to evaluate the impact of the use of amoxicillin-clavulanate on completion rates of CE in patients who had endoscopic placement of the capsule endoscope.
Methods: A retrospective chart review was conducted for patients who received VCE at our center during the years 2009 to2015. Parameters were assessed to determine predictors of capsule completion, including route of administration, BMI, inpatient status, abdominal surgical history, use of prokinetic agents, indication for CE, concurrent colonoscopy, comorbidities, small bowel transit time (SBTT), completion of CE, and findings. Paired T-test was used to compare groups. This study was approved by the Institutional Review Board at our institution.
Results: A total of 196 patients (46% male) underwent CE from 2009–2015 at our institution. Endoscopic placement of the capsule was performed in 72 patients and 124 patients orally ingested the capsule. Twenty-seven of 72 (37.5%) patients received prokinetic medications (amoxicillin-clavulanate [78%], erythromycin [18%], or metoclopramide [4%]) following endoscopic placement of capsule. Eighteen of the 27 patients (67%) who received prokinetic agents had successful completion of CE. Of the 45 patients who did not receive prokinetic agents following endoscopic placement, 32 patients had successful completion of CE (71%). There was no significant difference in rate of completion between patients receiving amoxicillin-clavulanate and those who did not. There was no significant difference in completion of CE between patients receiving prokinetics overall and those who did not. There was no significant difference in mean SBTT in patients who received prokinetics and in those who did not (p
= 0.8). When comparing predictors of CE completion in patients who did or did not receive prokinetics, there was no statistical significance in BMI (p
= 0.3), concurrent colonoscopy (p
= 0.4), history of abdominal surgery (p
= 0.2), inpatient status (p
= 0.2), or presence of comorbidities (p
Conclusions: The use of amoxicillin-clavulanate does not significantly increase the rate of CE completion or decrease SBTT in patients undergoing endoscopic placement of capsules. Inpatient status, BMI, abdominal surgical history, concurrent colonoscopy, and comorbidities cannot be used as predictors of CE completion. Further investigation into specific populations of patients who may benefit from promotility agents in CE is warranted.
99 THE INCREASING PREVALENCE OF GASTROESOPHAGEAL REFLUX DISEASE IN CHILDREN
Vaidotas Urbonas, Skirmante Brazdeikyte, Julija Cervinskiene, Jurate Sakalinskiene, Vilnius University Children's Hospital, Vilnius, Lithuania
Objective: The prevalence of gastroesophageal reflux disease (GERD) is increasing especially in the developed countries. The etiology of the disease in most cases is unknown. The hallmark of GERD is erosive esophagitis. The aim of this study was to evaluate the prevalence and the trend of the severity of erosive esophagitis in the country where life style during the past 25 years has changed greatly.
Methods: Retrospectively we investigated 2090 children (0 to 18 years of age) with erosive esophagitis. The diagnosis was made after upper endoscopy performed at Vilnius University Children's Hospital during the years 2000 to2015. Esophagitis was diagnosed when erosive lesions were seen on endoscopy. Modified Savary-Miller scale was used to grade erosive esophagitis.1 Children with combustion of the esophagus orimmunodeficiency were excluded. The same five physicians performed all endoscopies.
Results: During 2000–2008 years the total number of upper endoscopies was similar, but from 2010 the total number increased (Table 1). The prevalence of erosive esophagitis during 2000–2015 years was increasing, except 2015. The biggest prevalence was in the 13–18 years’ group. The severity of erosive esophagitis didn’t change during 2000–2015 years. The prevalence of erosive esophagitis was slightly more frequent among boys.
Conclusions: 1) The prevalence of erosive esophagitis during 2000–2015 years was increasing, except 2015 2) The severity of erosive esophagitis was mostly grade 1 and didn’t change during 2000–2015 years.
References: 1. Thomson M. Esophagitis. In: Pediatric Gastrointestinal Disease. Eds. Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins JB, BC Decker Inc., Ontario, 2000, 297-316.
100 ENDOSCOPIC FINDING WITH CLINICAL MANIFESTATIONS HELICOBACTER PYLORI INFECTION IN CHILDREN WITH RECURRENT ABDOMINAL PAIN AT DR. HASAN SADIKIN GENERAL HOSPITAL BANDUNG,INDONESIA.
Yudith Setiati Ermaya, Dwi Prasetyo, Faculty of Medicine, Universitas Padjadjaran, Dr. Hasan Sadikin General Hospital, Bandung, West Java, Indonesia
Background: Prevalence of recurrent abdominal pain (RAP) 10–30%; RAP is abdominal pain that occurs three times or more within 3 months that can interfere with daily activities for children with functional or organic causes. Organic causes include infection with Helicobacter pylori (H. pylori). The aim of this study was to assess the characteristic endoscopic findings with clinical manifestations of H. pylori infection.
Method: A cross-sectional study was conducted on 30 patients with complaints RAP children who came to Dr. Hasan Sadikin General Hospital Bandung during the period April 2015 toJanuary 2016 and doing endoscopic procedure with biopsy for histology finding.
Results: 30 children with RAP, comprising 14 (47%) boys and 16 (63%) girls, median age 12 years; the clinical manifestations are RAP 14 (47%) found most, endoscopic findings 23 (77%), erosion and ulcers 4 (14%). Positive H. pylori infection was seen in 90% of subjects., Duration of RAP is highest at 3–6 months. Symptom make the clinical manifestation 13 (43.3%).
Conclusion: Clinical manifestation H. pylori in children with recurrent abdominal pain show that increase at endoscopic finding worse.
Endoscopy, infection of H. pylori, recurrent abdominal pain
∗101 ROLE OF VIDEO CAPSULE ENDOSCOPY IN PATIENTS WITH BIALLELIC MISMATCH REPAIR DEFICIENCY SYNDROME: REPORT FROM THE INTERNATIONAL CONSORTIUM
Yuto Shimamura1,5, Carol Durno2, Catharine Walsh2,5, Shlomi Cohen3,5, Melyssa Aronson4,5, Uri Tabori2,5, Paul Kortan1,5,1St. Michael's Hospital, University of Toronto, Toronto, ON, Canada,2Hospital for Sick Children, University of Toronto, Toronto, ON, Canada,3gDana-Dwek Children's Hospital, Tel-Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel,4Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada,5The International BMMRD Consortium
Background: Biallelic mismatch repair deficiency (BMMRD) is caused by biallelic mutations in mismatch repair genes and manifests features of gastrointestinal (GI) polyposis, early-onset brain, hematological, and GI cancers. The International BMMRD Consortium and the European Consortium Care for CMMRD recommend video capsule endoscopy (VCE) starting at 8 and 10 years of age, respectively. The small bowel phenotype is not well described and the utility of VCE remains unstudied.
Objectives: To evaluate the usefulness and clinical impact of VCE for small bowel polyp and cancer surveillance in BMMRD patients.
Methods: Patiets from 11 countries were included in the International BMMRD Consortium dataset after identification of mutations and/or immunohistochemical confirmation. Treating physicians were contacted and VCE report data extracted using a standardized template.
Results: @ Fifty-eight patients (37 kindreds) were identified. Mutations included MLH1 (n = 4), MSH2 (n = 5), MSH6 (n = 14), and PMS2 (n = 35). In total, 38 VCEs were completed on 17 patients. Median age of first VCE was 14 years (range: 4–31). The number of VCEs performed on each patient ranged from 1 to 7. Polyps were identified in 24 VCEs (63%) on 10 patients. First polyp was detected at the median age of 14 (range: 4–17). Twelve VCEs prompted further investigations, including 5 laparotomies and 2 double balloon enteroscopies. Five patients in the consortium, including 3 siblings, had small bowel adenocarcinomas (SBC) with a median age of diagnosis of 13 (range: 11–33). VCE detected the cancer in 1 patient as it revealed multiple polyps which led to intraoperative enteroscopies revealing a duodenal cancer. Cancers were detected by other imaging modalities in the remaining 4 cases. Three patients with a history of small bowel cancers underwent VCE; polyps were identified in 10 of 12 VCEs. Ten VCEs (28%) were incomplete due to slow bowel transit secondary to previous GI surgery; none required capsule removal.
Conclusions: Small bowel polyps were identified in nearly two-thirds of the surveillance VCEs. Polyps were common in patients with previous small bowel cancer; therefore, a higher index of suspicion is needed for these patients. The rate of incomplete VCE study was high, especially in patients with a history of previous abdominal surgery, which may suggest a risk of capsule retention. VCE can detect polyps in the BMMRD population. A larger sample size is needed to assess the accuracy of concurrent evaluation using other modalities and thereby, to build an evidenced-based small bowel surveillance protocol for patients with BMMRD syndrome.
104 A LACTOBACILLUS GG AND MICRONUTRIENT CONTAINING MIXTURE IS EFFECTIVE IN PREVENTING NOSOCOMIAL INFECTION IN CHILDREN: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL.
Eugenia Bruzzese1, Alfredo Guarino1, Andrea Lo Vecchio1, Maria Cristina Fedele1, Dario, Bruzzese1, Sara Viscovo1, Antonietta Giannattasio1, Claudia Mandato2, Paolo Siani2,1University of Naples Federico II, Naples, Italy,2Santobono Children's Hospital, Naples, Italy
Background: Nosocomial infections are a major public health issue and preventive strategies using probiotics and micronutrients are being evaluated.
Aim: To investigate the efficacy of a mixture of Lactobacillus GG (LGG) and micronutrients in preventing nosocomial infections in children.
Methods: A randomized, double-blind, placebo-controlled trial was conducted in hospitalized children. Children (6 months to 5 years of age) received LGG (6x109CFU/day) with vitamins B and C and zinc or placebo, for 15 days, starting on the first day of hospitalization. The incidence of gastrointestinal and respiratory nosocomial infections after discharge was determined by follow-up telephone call at 7 days. The incidence of infections in the long erm was evaluated through a telephone call after three months from the discharge. Written informed consent was obtained from the parent of each child included in the study. This trial was registered at Clinical Trial.gov (NCT02558192).
Results: Ninety children were enrolled and completed the follow-up. 18/90 children had a nosocomial infection (20%), of which 4/45 children (9%) were in the treatment group and 14/45 (31%) were in the placebo group (p
= 0.016). Specifically, 2/45 (4%) children in the treatment group vs. 11/45 (24%) children in the placebo group (p
= 0.007) presented with diarrhea. No difference was observed in the incidence of respiratory tract infections between the two groups. The duration of hospitalization was significantly shorter in the treatment group (3.9 days ± 1.7 vs. 1.2 ± 4.9 days; p
= 0.003). During the follow-up period, a total of 11/45 (24.4%) children in the treatment group had at least one episode of infection compared to 22/45 (48.9%) children in the placebo group (p
= 0.016). The main effect was observed in the incidence of gastrointestinal infections (5/45 vs.. 14/45, p
Conclusions. A mixture containing LGG and micronutrients is effective in reducing the incidence of nosocomial infections, mainly gastrointestinal infections and the protective effect is sustained over time. This study supports the hypothesis that the administration of LGG and micronutrients may provide a valid strategy to prevent hospital-acquired infections.
105 PREVALENCE OF SYMPTOMS ASSOCIATED WITH SLEEP-DISORDERED BREATHING AMONG PATIENTS SEEN IN A PEDIATRIC GASTROENTEROLOGY CLINIC
Grace Felix, Ann Scheimann, Carmen Cuffari, Wikrom Karnsakul, Kathleen Schwarz, Darla Shores, Christine Karwowski, Lisa Santo Domingo Johns Hopkins Hospital, Baltimore, MD, USA
Background: Sleep-disordered breathing (SDB) in children is associated with daytime functional decrements in cognitive performance and behavioral regulation. As recently published data has shown a relationship between obstructive sleep apnea (OSA). a manifestation of sleep disordered breathing and the severity of non-alcoholic fatty liver disease, we sought to identify the prevalence of symptoms of sleep-disordered breathing among patients seen in the pediatric gastroenterology clinics.
Methods: IRB retrospective chart review of children seen in both urban and suburban Johns Hopkins Pediatric Gastroenterology Clinics between 7/2015–4/2016. Data collected included: anthropometry, labs, relevant clinical information in addition to sleep questionnaire results. The Sleep-Related Breathing Disorder Questionnaire is a validated measure for SDB extracted from the Pediatric Sleep Questionnaire developed by Chervin et al. Questionnaire scores > (or equal to) 0.33 are considered positive and suggestive of high risk for a pediatric sleep-related breathing disorder. Statistical analyses including Mann-Whitney and Chi-Square were used where appropriate.
Results: A total of 104 children were eligible for participation in the study. The majority of diagnoses at presentation were constipation, abdominal pain or reflux. Median population age was 8.4 + 5.1 years, 50% of the population was male. Ethnicity was 62% Caucasian/23% African American/7% Hispanic/8% other. Median BMI Z-score was 1.23 + 1.41. 17/104 children 16.4% of the population had abnormal questionnaire results. There was no difference in mean age, or sex distribution across groups stratified by ethnicity or sleep questionnaire scores. Surprisingly, there was no difference in BMI z-score across sleep questionnaire groups. There was a higher prevalence of sleep disordered breathing among African American (30%) vs. Caucasian children (11%) p
= 0.029 and a trend toward significance among children with constipation p
Conclusion: A significant number of children seen in the GI clinic had evidence of sleep-disordered breathing on assessment without relation to weight status. Further evaluation is warranted re: impact upon long-term disease management.
106 LONGITUDINAL PROFILE OF NEUTRAL HUMAN MILK OLIGOSACCHARIDE FROM THREE URBAN POPULATIONS: THE GLOBAL EXPLORATION OF HUMAN MILK (GEHM) STUDY
Ardythe L. Morrow1, Ceng Chen2, Allison Cline1, Ying Yu1, Jessica G. Woo1, Yong-Mei Peng3, M. Lourdes Guerrero4, Guillermo M. Ruiz-Palacios4, David S. Newburg2,1Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA,2Boston College, Boston, MA, USA,3Shanghai Children's Hospital, Shanghai, China,4National Institute of Medical Sciences and Nutrition, Mexico City, Mexico,
Background: Breastfeeding is recommended as the optimal method of infant feeding. Human milk oligosaccharide (HMO) is a major component of human milk, but its composition varies between mothers, and this variation has been reported to influence infant health outcomes, including diarrhea, allergy, and growth or malnutrition. The HMO composition of milk varies with maternal FUT2 (“secretor”) and FUT3 (Lewis) genetics and the relative abundance of type 1 and non-type 1 precursor molecules. To define the conserved and variable patterns in HMO composition over lactation, we compared 12 neutral HMOs in milk collected at standardized times from 375 urban mothers with term deliveries representing different ancestry groups, and examined the potential impact of maternal clinical and demographic factors.
Methods: We analyzed the HMO composition of milk from 120 white and African-American mothers in Cincinnati, Ohio; 135 mothers in Mexico City, Mexico of mestizo ancestry; and 120 Chinese mothers in Shanghai, China. Samples and data were collected at 2, 4, 13 and 26 weeks of life following a standardized protocol. A total of milk 956 samples were analyzed by LC-MS. Maternal and infant clinical factors included birth weight, gestational age, delivery mode, maternal race/ethnicity, maternal prepregnancy BMI, and pregnancy weight gain. Statistical modeling of HMOs was conducted using generalized estimating equations (GEE) to compare the cohorts accounting for maternal and infant characteristics and repeated samples per mother.
Results: Neutral HMOs were higher in Cincinnati milk compared to the other cohorts (p < 0.001) and decreased over the first 6 months of lactation in all three cohorts (p < 0.001). The cohorts differed in the abundance of individual HMOs and in the percent classified into three milk oligosaccharide types: 1) secretor and Lewis positive mothers, whose milk included all HMOs; 2) secretor positive but Lewis negative mothers, whose milk lacked ɑ1,4 -linked fucosylated HMOs; and 3) secretor negative mothers, whose milk lacked ɑ1, 2-linked fucosylated HMOs. Cincinnati milk had more type 1 and Lewis HMOs; Mexican milk had more non-type 1 and secretor HMOs. The HMOs of Cincinnati white mothers had significantly more Lewis HMOs (p < 0.001) than African-American mothers or mothers from other sites. In all cohorts, type 1 and secretor HMOs decreased over lactation. In contrast, non-type 1 HMOs and Lewis HMOs remained consistent or increased over lactation in all cohorts. Maternal and infant clinical factors were not associated with HMO composition.
Conclusions: Neutral HMOs vary between populations due to genetic differences and the importance of type 1/non-type 1 chains. Nevertheless, HMO composition changes over lactation in a pattern that is consistent across populations. These systematic differences in HMOs could influence infant gut health and development, and requires functional studies.
107 ASSOCIATION OF EOSINOPHILIC ESOPHAGITIS AND ASTHMA
Carlos Camacho, Vylma Velazquez, Melissa Vicente, Claudia Sierra, Paola Zayas, Hospital Episcopal San Lucas, Ponce, Puerto Rico, USA
Introduction: Asthma is a chronic disease of the airways and it is the most common chronic disease of childhood. Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder characterized by eosinophilia in the esophageal mucosa that causes feeding difficulties, regurgitation, vomiting, abdominal pain, dysphagia, and food impaction. EoE and asthma, as well as other atopic diseases, are frequently associated and have a number of similarities in their pathogenesis.
Objective: This project will help to estimate the prevalence of bronchial asthma in patients with EoE, and to estimate the association between severe eosinophilic esophagitis and severe asthma.
Methods: This is a cross-sectional study. The interview will include a question to identify which patients also have a diagnosis of bronchial asthma. Those patients with bronchial asthma will be assessed using the AAP Asthma Severity Scale and a history of bronchial asthma medications will also be obtained. For those patients who have both bronchial asthma and EoE, a comparison analysis will estimate the association between severe EoE and severe asthma, using the Prevalence Ratio and its corresponding 95% Confidence Interval.
Results: 30 patients with EoE participated in our study, with a male predominance 63% (n = 19). Age distribution was more prevalent in the 6–10-years’ group (n = l 4). Half of the patients evaluated were asthmatic, 43% had mild intermittent asthmatic and 7% were persistent asthmatics. Almost all patients were diagnosed with asthma (4 years old) previous to EoE diagnosis (9 years old); average time frame between asthma and EoE diagnosis was almost 5 years. There was no relation between the total eosinophil count in the tissue biopsy and the presence of asthma, and there was no correlation between the severity of both conditions that can be attributable to the eosinophil count in the esophageal biopsy.
108 IODINE NUTRITION DURING PREGNANCY AND RELATED NEONATAL PHYSICAL DEVELOPMENT IN SHANGHAI
Qingya Tang, Huijuan Run, Yejun Lu, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Objective: To monitor iodine nutrition of women during late pregnancy in Shanghai a Coastal Area in China, and to examine the correlation between maternal urine iodine concentration and newborn physical development.
Method: We used the prospective cohort study data from the women during late pregnancy(28–34 week) who accepted the follow-up intervention in the Department of Clinical Nutrition in Shanghai Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine between December 2014 and February 2015. All participants collected a spot urine sample three times every two weeks. Study participants completed a iodine-related food frequency method and 24-hour food diary and that was administered twice at 28̈C34 weeks of gestation. TSH in neonatal heel blood was analyzed 72 h after birth.
Results: 151 women were recruited into the study. Data from the study showed all pregnant women (n = 151) had a median UI concentration of 100.0 μg/L25th–75th percentiles: 64.7∼155.6 μg/L). In sequence, urinary iodine levels of 150 μg/L, 249 μg/L were defined as the cut-off points iodine insufficient, adequate, more than adequate; all subjects were divided into three subgroups, 76.8% (n = 116), 19.2% (n = 29) and 4.0% (n = 6), respectively.
Subgroup analysis showed that the iodine insufficient group (n = 116) compared with the adequate iodine group (n = 29), their birth weight, length and placental weight were [(3295 ± 370) g vs. (3397 ± 504) gp = 0.311][50.0 (2.0) cm vs. 50.0 (2.5) cmp = 0.316] and [(636 ± 89)g vs. (658 ± 104) gp = 0.268] respectively, and there were no significant difference between the two subgroups. In addition, analysis of the head circumference of newborns [34.5 (1.0) cm vs. 34.5(1.0) cm, p = 0.316] and TSH in neonatal heel blood [(4.0 ± 1.9)g vs. (3.9 ± 2.1) mIU/Lp = 0.895], no significant difference between the two subgroups (Table 1).
Conclusion: According to WHO standards, the rate of iodine deficiency (UI<150 μg/L) in pregnant women in Shanghai in late pregnancy is 76.8%. The results of the study suggested that there was no significant difference between the status of iodine nutrition during pregnancy and fetal development. Therefore, the standard was applicable to Chinese pregnant women. There is a need to have more multi-center studies confirmed.
109 THE APPLICATION AND EPIDEMIOLOGICAL RESEARCH OF XTAG GASTROINTESTINAL PATHOGEN PANEL MULTIPLEX PCR IN THE DIAGNOSIS OF CHILDREN PERSISTENT AND CHRONIC DIARRHEA
Zhifeng Liu, Yu Jin, Chunli Wang, Bixia Zheng, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, China
Objective: To Investigate the application value of xTAG gastrointestinal pathogen panel (xTAG GPP) multiplex PCR in the early diagnosis of children with persistent and chronic diarrhea, and to understand the epidemiology of intestinal diarrhea pathogens.
Methods: One hundred and ninety-nine specimens were collected in Nanjing Children's Hospital, Nanjing Medical University, from October 1, 2014 to September 30, 2015. The xTAG GPP Multiplex PCR Assay was compared with the traditional methods (culture, rapid enzyme immunoassay chromatography, microscopic examination) and modding the statistical analysis.
Results: The positive rate of 199 patients with diarrhea specimens was 72.86% (145/199) the proportion of girls and boys was 1:1.39; the average age was 13 months. The virus detection rate was 48.7%; Rotavirus A was the most common organism detected (34.6%), concentrated in winter, and prevalent in children. Norovirus GI/GII was second, at 20.6%. The positive rate of bacteria was 40.2%, and Campylobacter (22.11%, 44/199) was most frequently detected. With C. difficile toxins A/B and Salmonella detected 44 and 17 samples, respectively. Infections with Shigella occurred 4 times, E. coli O157 was only detected once. There were three samples with parasitic (1.51%), two samples were positive for Entamoeba histolytica, one for Cryptosporidium. Adenovirus 40/41, STEC, ETEC, Giardia, Yersinia enterocolitica and Vibrio cholera were not detected. All of them did not have obvious distribution followed by season and population. Totally 86 (43.2%) infected specimens with single pathogen were detected. There were 57 co-infections (28.64% of samples) of viruses and/or bacteria and/or parasites. Co-infections involved 29 double infections (23.62%) samples, 9 triple infections (4.52%) and 2 quadruple infections (0.5%). Norovirus GI/GII was found to have the highest involvement in co-infections 30 (15.08%).
Conclusions: xTAG GPP multiplex PCR is simple, sensitive, specific and can be used as a quick way to diagnose children's persistent and chronic diarrhea. Diarrhea pathogen has significant characteristics according to season and population.
Keywords: Persistent diarrhea; Chronic diarrhea; Nucleic acid amplification techniques; Viruses; Bacteria; Parasites
110 SiO2 NANOPARTICLES MODIFIED WITH SELF-ASSEMBLED MONOLAYER: TOXICOLOGY STUDIES IN A MOUSE MODEL
Chun-Yan Yeung1, Wai-Tao Chan1, Mei-Lien Cheng1, Jen-Shiu Chiang Chiau1, Hung-Chang Lee1, Shao-Yi Hou2,1MacKay Children'sHospital, Taipei, Taiwan,2National Taipei University of Technology, Taipei, Taiwan
Background: Nanoparticles (NPs) are studied for their potential applications in bioassay, diagnosis, and therapy in recent decades. For example, nanogold and gold-shell NPs have been applied in drug delivery and photothermal therapy, respectively. However, little research focuses on NPs of non-gold materials in vivo. In this study, SiO2 NPs modified with self-assembled monolayer is utilized in an animal model. The aim of this study is to investigate the toxicity of SiO2 NPs in mice by bio-safety experiment and LD50 toxicity test.
Material and methods: The modified NP has a size of 150 nm. LD50 toxicity test is determined by serial doses (0, 1, 2, 2.5, 5, 10, 100, 200 and 300 mg/kg body weight) of SiO2 NPs. Male BALB/c mice received SiO2 NPs by a single dose of tail intravenous injection and were sacrificed 14 days later.
Results / Body Weight: The body weight was not significantly different in each group after 14 days. Serum Biochemistry: BUN was significantly decreased at all concentration groups to control, except the 2.5 mg/kg group. GPT, CPK were mostly higher than control. GOT, CRE and T-BIL were mostly lower than control;TP and ALB were similar to control. However, those serum levels were within normal limits.
Histopathologic Analysis: Liver, brain, heart, lung, kidney and spleen were examined under microscopy with no histopathologic lesions seen.
Conclusion: All mice survived until sacrificed. Various organs were found to have no nanoparticles-related pathological reactions. SiO2 nanoparticles caused no apparent toxicity under the present experimental conditions.
111 GENDER DISPARITY AMONG PEDIATRIC GASTROENTEROLOGISTS IN NORTH AMERICA AND AUTHORSHIPS IN MAIN PEDIATRIC JOURNALS
Vi Goh, Claudio Morera, Boston Medical Center, Boston University, Boston, MA, USA
Background: Authorship in peer-reviewed medical journals is a marker for success in academic medicine.
Objective: To determine the representation of female physicians in the field of pediatric gastroenterology and authorships of original research in common journals for pediatric gastroenterologists.
Subjects: Members of North America Society of Pediatric Gastroenterology, Nutrition, and Hepatology (NASPGHAN) who were practicing in North America were included in the study and classified by gender. All first and senior authors of pediatric gastroenterology original research published in the years 2005, 2009, and 2013 in main pediatric journals with pediatric gastroenterology publications were also classified by gender.
Results: Members of NASPGHAN practicing in North America increased from 1,016 in 2005 to 1,484 in 2009 and 1,670 in 2013. We evaluated 3033 original research articles. A total of 273 articles met the criteria of 1) pediatric gastroenterology theme; 2) first author, senior author or both female; and 3) based in North America. There were no significant differences in the proportion of female first authors over the years (p > 0.05). There are significantly fewer female senior authors compared to the proportion of pediatric gastroenterologists in North America in 2013.
Conclusions: The proportion of female pediatric gastroenterologists is increasing in North America. The proportion of female senior authors is significantly lower than the proportion of practicing pediatric gastroenterologists in 2013.
112 FEEDING DIFFICULTIES OF PATIENTS WITH FOOD ALLERGIES IN A PEDIATRIC GASTROENTEROLOGY REFERENCE CENTER
Silvana Dadan, Wilson Daza Carreño, Michelle Higuera Carrillo, Gastronutriped, Bogota, Cundinamarca, Colombia
Introduction: Food allergy (FA) is an immune response to a food antigen: IgE mediated, non-IgE, or mixed. Patients with FA may have eating disorders; however, studies that assess this relationship are limited. The purpose of this study was to describe the types and distribution of feeding difficulties in patients with a FA in the Gastroenterology, Hepatology, and Nutrition Reference Center (Gastronutriped) in Bogota, Colombia.
Methodology: A retrospective study was performed, which involved patients ages 0–18 who were diagnosed with FA and feeding difficulties, attended at Gastronutriped from 2013 to 2015. Patients with genetic syndromes, malformations of the gastrointestinal tract, autism spectrum disorders, and hypoxic encephalopathies were excluded. The data was extracted from medical records. The analysis was made using Stata 13. The description of continuous variables was performed with mean or median, with their respective measure of dispersion (standard deviation or interquartile range), according to their distribution. Discrete variables were expressed as proportions. For the comparison of the variables of interest, the Fischer exact test was applied, and a value of p < 0.05 was considered significant.
Results: From a total of 644 patients, 109 (16.92%) were diagnosed with FA. Of these, 40 (36.69%) had an eating behavior disorder (EBD), and the most frequent manifestation was alteration of the appetite. In patients with FA and EBD, a mixed mechanism FA prevailed (62.5%), the most frequent clinical expression was eosinophilic esophagitis (37.5%), and selective appetite was the most common symptom. In patients with FA without EBD, the group with IgE-mediated FA was dominant (52.17%). Mixed mechanism FA was associated with increased prevalence of eating disorders (p < 0.009). Feeding difficulties were more frequently found in males (22, 55%) and infants (31, 77.5%), with an average age of 13.3 months. More than half of the patients with FA and EBD (55%) exhibited a normal nutritional status. Risk factors for eating disorders were found: prior hospitalization (52.5%), use of catheters, nasogastric or orogastric feeding (15%), and history of prematurity (5%).
Conclusions: Feeding difficulties occur in parallel or as a result of FA. They seem to be more associated with the mixed mechanism, and within it, with eosinophilic esophagitis. In these particular patients, selective appetite predominated. However, the limited numbers of patients in our study seems to call for wider studies. For this approach, an interdisciplinary system is needed, because of the great impact that both phenomena have on the family and on the psychosocial level.
113 ACIDIC HUMAN MILK OLIGOSACCHARIDES VARY ACROSS CHINESE, MEXICAN, AND AMERICAN POPULATIONS AND OVER LACTATION
David S. Newburg1, Ceng Chen1, Allison Cline2, Ying Yu3, Jessica G. Woo2, Yong-Mei Peng3, M. Lourdes Guerrero4, Guillermo M. Ruiz-Palacios4,1Boston College, Newton, MA, USA,2Cincinnati Children's Hospital, Cincinnati, OH, USA,3Shanghai Children's Hospital, Shanghai, China,4National Institute of Medical Sciences & Nutrition, Mexico City, DF, Mexico
Background: Human milk oligosaccharides (HMOs) inhibit pathogens, promote colonization through a prebiotic effect, and inhibit inflammation of the intestinal mucosa. The content of HMOs varies qualitatively and quantitatively among individuals and over the course of lactation.
Objective: To compare the acidic HMOs composition of milk from mothers in Cincinnati, OH, Shanghai, China, and Mexico City, Mexico over the course of early lactation.
Methods: Cohort- 120 mothers, 760 milk samples per site as part of the Global Exploration of Human Milk (GEHM) study. Eligibility required healthy, singleton, term delivery and > 5% of feedings from breast milk for at least 3 months. Milk samples were collected between 9AM-1PM at 2, 4, 13 and 26 wks postpartum using Medela Symphony breast pumps, and represented the contents of one breast that was not used for feeding within two hours of pumping. Analysis - defatted, deproteinated, reduced, and filtered samples were analyzed by LC-MS. Oligosaccharides were separated on a Hypercarb graphitized column with gradient of acetonitrile/0.02%aq ammonium acetate and detected by electrospray mass spectrometry with a positive target of [M-H]+ and [M-2H]2+ ions.
Results: Total oligosaccharides decreased over lactation, from 5.8 (week 2) to 2.8 g/L (week 26, p < 0.001). However, the most rapid decline in HMOsoccurred in the acidic oligosaccharide fraction, from 2.4 (week 2) to 0.4 (week 26, p < 0.001). Milk from Shanghai was significantly lower than the other two sites in total HMOs(at month 1: 4.1 vs. 5.1 g/L, p < 0.001). The most abundant individual acidic HMOs across the populations were 3’-sialyllactose (3'SL), 6’-sialyllactose (6'SL), and disialyllacto-N-tetraose (DSLNT). Comparing populations, 3'SL was higher (p < 0.001), 6'SL was lower (p < 0.001), and DSLNT was lower (p < 0.001) in Mexican than Cincinnati or Shanghai mothers. The concentrations of 6'SL and DSLNT declined, whereas 3'SL did not decline, over the first 26 weeks of lactation.
Conclusions: Concentrations of different HMOs differ among populations, and change over the course of lactation. The biological ramifications of these differences warrant closer investigation.
114 INCIDENCE AND CHARACTERISTICS OF ANORECTAL MALFORMATIONS IN HISPANIC CHILDREN ON THE USA-MEXICO BORDER
Mohamed A Shaban1, Eduardo Rosas Blum1, Ajay Reddy1, Sandra Aziz2, William Spurbeck1, Robert Johansson3,1Texas Tech University HSC El Paso, El Paso, TX, USA,2Paul L. Foster School of Medicine. Texas Tech University HSC El Paso, El Paso, TX, USA,3El Paso Children's Hospital, El Paso, TX, USA
Background: Anorectal Malformations (ARMs) are widely known as the range of congenital malformations involving the gastrointestinal, urogenital, and/or the gynecological anatomy. These affect male and females with a slightly greater predominance in males and occur in approximately 1:5000 live births. ARMs are classified as: high (anorectal agenesis and rectal atresia), intermediate (agenesis anomalies), and low (perineal and vulvar malformations). ARMs can be isolated or associated with other syndromes. Review of the current literature suggests that there is poor characterizations of ARMs in the Hispanic population.
Objective: Determine the incidence of ARMs in Hispanic children over a 3-year period and to describe the characteristics of these malformations.
Methods: We performed an IRB-approved chart review of all patients with ARMs at the Pediatric Surgery outpatient clinic from January 2012 to December 2015. Demographic data, type of malformations, associated syndromes, and long-term complications were recorded. An incidence rate was also calculated. Patients older than 4 years of age and non-Hispanic patients with ARMs were excluded.
Results: A total of 57 patients’ charts were reviewed and 24 patients were included in the study. Using the US Census Bureau birth data for El Paso County, the incidence rate for ARMs was approximately 1:1428 births. Our cohort included 16 males and 8 females. Twenty-one patients had major ARMs which included: imperforated anus (n = 20), Perianal fistulas (n = 6), cloacal malformation (n = 4), and rectourinary fistulas (n = 5). Only 3 patients had minor ARMs that included: bowel atresia, ectopic anus, and anorectal stenosis. The most common post-surgical complication was poor wound healing (22.7%). There were 14 patients that had multiple ARMs: 12 patients had 2 ARMs, 1 patient had 3 ARMs and 1 patient had 6 ARMs. In patients with major ARMs, 72.7% were isolated cases and 6 cases (27.2%) were associated with a syndrome. The most common associated syndromes were VACTERL, Down's syndrome, DiGeorge syndrome, Chromosome 9 deletion and Trisomy 16 mosaicism. Patients with minor ARMs had an associated syndrome in 66% of the cases. Constipation was the most common long term complication for ARMs (43%), followed by fecal incontinence (14%), and persistent rectal bleeding (8%).
Conclusion: Based on our study, we are able to demonstrate an increased incidence of ARMs in Hispanic children born on the US-Mexico border. The most frequently found ARMs in our population were imperforated anus, perianal fistulas, and cloaca malformation. The vast majority of ARMs were isolated defects. Constipation and fecal incontinence were the most common long term complications. Additional studies are needed to determine the reason for the increase incidence of ARM in this population.
115 LEVELS OF AND INTERRELATIONS BETWEEN MAJOR HUMAN MILK OLIGOSACCHARIDES IN BREAST MILK FROM THE LIFE COHORT
Erik Eckhardt1, Sean Austin1, Chiara Nembrini1, Jürgen Kratsch2, Norbert Sprenger1,1Nestlé Research Center, Lausanne, Vaud, Switzerland,2University of Leipzig, Leipzig, Sachsen, Germany, Wieland Kiess, University of Leipzig, Leipzig, Sachsen, Germany,
Backgroun /Aim: Human milk oligosaccharides (HMOs) are among the most abundant components of human milk, however the majority of these oligosaccharides is not digestible by the infant. HMOs can act as prebiotics for the infant's microbiota and contribute to the beneficial effects of human milk. Depending on the mother's genotype, types and abundance of HMOs vary, with most decreasing in concentration as lactation progresses. Besides genotype dependence, not much is known about the regulation of HMO synthesis. We quantified some of the major HMOs in breast milk to better understand their interrelations and their regulation to eventually study their relations with clinical health measures in infants.
Methods: Milk samples at 3 months of lactation were obtained from 156 volunteers who participated in the ‘LIFE’ cohort in Leipzig, Germany. Using a validated UHPLC based method, 10 different HMOs were quantified in each sample.
Results: Most milk samples contained detectable amounts of the 10 measured HMO, except for A-tetrasaccharide, for which 64.5% of samples had levels below the limit of detection (4.9 mg/kg) and 68% had levels below the limit of quantification (LOQ) of 20 mg/kg. For Lacto-N-neofucosylpentaose, 32% of samples were below LOQ (12 mg/kg). Average values for the 156 samples are listed in order of increased concentration (mg/kg): Lacto-N-neofucosylpentaose (LNnFP; 17), A-tetrasaccharide (PI; 46), lacto-N-fucosylpentaose-V (LNFP-V; 70), 3’ sialyllactose (3'SL; 144), Lacto-N-Neotetraose (LNnT; 148), 6’ sialyl-lactose (6'SL; 167), lacto-N-fucosylpentaose-I (LNFP-I; 528), Lacto-N-Tetraose (LNT; 607), 3-fucosyllactose (3-FL; 1044), and 2’-fucosyllactose (2’FL: 1882). Of the 156 samples, 20 contained hardly any of the usually abundant 2’-FL, indicating inability to synthesise α-1,2- fucosylated oligosaccharides. Synthesis of α-1,2- fucosylated oligosaccharides is performed by fucosyltransferase-2 (FUT2), individuals who are unable to secrete this enzyme are known as “FUT2 non-secretors”. We observed that 2’FL levels were strongly correlated with LNFP-I as expected from their FUT2 dependence. Interestingly, 2’FL and LNFP-I also showed a positive correlation with LNnT, but not with LNT, one of the main acceptors substrates of FUT2, and an inverse correlation with 3-FL, which is fucosylated but via different linkage.
Conclusion: HMO levels in milk samples from a German cohort (LIFE) show similar levels as found in the literature. Of the included 156 subjects, 12.8% were non-secretors. When FUT2 is functional (secretor mothers), high levels of 2’FL and LNFP-I are produced, while when FUT2 enzyme is dysfunctional (non-secretor mothers), other fucosyltransferases like FUT3 lead to the synthesis of higher levels of 3-FL.
116 CLINICAL PRACTICE GUIDE FOR THE DIAGNOSIS AND COMPREHENSIVE CARE OF CHILDREN WITH FUNCTIONAL CONSTIPATION
Fernando Sarmiento, Diana Victoria Mora Quintero, Claudia Sanchez, Andrea Rangel, Laura Gaitán, Efraim Bonilla, Hernando Gaitan, Universidad Nacional de Colombia, Bogata Dc, C/Marca, Colombia
Introduction: The present guide is the result of the implementation of the “Rapid Adaptation of Clinical Practice Guides” (RACPG), a strategy with no precedents. Chronic functional constipation is a frequent clinical situation in pediatric consultations and represents up to 25% of consultations with pediatric gastroenterologists.
General objective: To adapt a guide on chronic functional constipation in children from 0 to 18 years of age to unify the diagnosis and treatment of this pathology in our hospital.
Specific objectives: a) to implement recommendations based on the best clinical evidence for chronic functional constipation diagnosis and treatment;b) to provide direction in order to unify its management; c) to improve the quality of life of pediatric patients with this pathology; and d) to reduce costs for the current health system.
Methodology: With the counsel of trained personnel and the oversight of a Trials Search Coordinator from Cochrane Collaboration in Colombia, a systematic, highly sensitive search was conducted to identify Clinical Practice Guides (CPG) on chronic functional constipation diagnosis and treatment in children. The Developer Group (group of experts) with the methodologist reviewed the guides identified by the theme and with the MeSH words “children”, “idiopathic constipation”, “functional constipation”, and “guideline”, arriving at a selection of 27 documents. Titles that did not fulfill specific theme expectations were excluded, and the quality of each document was analyzed. Finally, a publication and its update was chosen because its characteristics coincided with the approaches of the group of experts, and the methodological requirements ofAGREE II were applied.
Results: With the selected guide from 2010 and its update in 2012, researchers proceeded to its adaptation following an established order: the guidelines to follow for those older and younger than 1 year were given, the critical points were established in terms of anamnesis, physical examination, pharmacological disimpaction treatment and non-pharmacological treatment. When points of discussion, uncontemplated topics, or inapplicable concepts for our context were found, consensus was reached based on the experiences and publications of Developer Group members, and resolved with the best evidence.
Discussion: With this adaptation, a quality, up-to-date, and methodologically sound Clinical Practice Guide has been achieved that will resolve difficulties by unifying criteria for the management of this pathology. It is obvious that the implementation of Clinical Practice Guidelines is indispensable for rational management, but the high cost and the time that must be spent are insurmountable obstacles on some occasions and in most low-income countries. In these circumstances, the RACPG becomes a valid and timely strategy to lower costs, save time, and optimize resources
117 IMPACT OF PROBIOTICS ON CONSTIPATION AND INTESTINAL MICROFLORA IN CHILDREN WITH FUNCTIONAL CONSTIPATION
Hsun-Chin Chao, Yung-Chia Hsu, Shih-Yen Chen, Chien-Chang Chen, Chang Gung Children's Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
Aim: To evaluate the effect of probiotics on the symptoms and intestinal microflora in pediatric patients with functional constipation.
Methods: A prospective, randomized controlled trial of probiotics in children (aged 6 months -10 years old) with functional constipation was performed. The enrolled patients were randomized into group A received magnesium oxide and probiotics (Clostridium butyricum Miyairi); group B received only magnesium oxide. Each patient was assigned the evaluation of constipation symptoms every day for 12 weeks and collection of fecal samples for detection of microflora at enrollment, 4 weeks, and 12 weeks.
The severity of constipation was quantified by scoring of constipation symptoms (ROME III criteria), and the reduction in scores was used to assess the therapeutic effect. Using real-time PCR, microflora (Clostridium butyricum Miyairi, Bacteroides fragilis, Bifidobacterium longum, Closdridium difficile, and Lactobacillus casei) was quantified from fecal DNA samples. Fecal samples of 40 healthy children were enrolled as control. An independent samples t-test for evaluation of differences between different group subjects was performed. A p < 0.05 is considered significant.
Results: A total of 81 participants [(A group, 41 cases (mean age: 3.7 ± 1.5 yrs, M/F17/24); B group, 40 cases (mean age: 4.0 ± 1.8 yrs, M/F 19/21)] were included in the study. After 4-week and 12-week treatment, the average increase of defecation frequency was significant in both groups [A: 1.6 (baseline), 4.5 (4 weeks), 5.9 (12 weeks); B: 2.4 (baseline), 3.6 (4 weeks), 4.9 (12 weeks)], while the increase was more significant in A group (p < 0.05). The mean scores of constipation symptoms were 7.0 ± 1.7 (baseline), 3.5 ± 2.1 (4 weeks), 1.7 ± 1.3 (12 weeks) in A group; and 6.5 ± 1.7 (baseline), 4.8 ± 1.9 (4 weeks), 2.6 ± 1.3 (12 weeks) in B group. Reduction of scores was significant in both groups, with more significant found in A group (p < 0.05). Comparing to the controls, the expressions of fecal Clostridium difficile and Lactobacillus casei was higher and lower in both groups, while no significant differences in the expressions of fecal Clostridium butyricum Miyairi and Bacteroides fragilis in both groups. After 12-week treatment, significant increase in the expressions of fecal Clostridium butyricum Miyairi was found in A group. Otherwise, significant reduction in the expressions of fecal Clostridium difficile was found in both groups (p < 0.05), while more significant reduction was found in A group. No significant increase in the expressions of fecal Bifidobacterium longum was found in both groups.
Conclusion: Probiotics help to reduce constipation symptoms in pediatric patients with functional constipation. Probiotics supplementation may increase intestinal probiotic microflora and decrease intestinal harmful microflora in children with constipation.
118 THE RELATIONSHIP BETWEEN ACTIVITY ENERGY EXPENDITURE AND BODY COMPOSITION IN SCHOOL-AGE CHILDREN
Huijuan Ruan1, Qingya Tang1, Xuelin Zhao1, Wei Cai2,1Xinhua Hospital,School of Medicine, Shanghai Jiaotong University, Shanghai, China,2Shanghai Institute for Pediatric Research, Shanghai, China
Aims: To assess the association between activity energy expenditure (AEE) and body composition in school-age children.
Methods: A total of 62 school-age children (8̈C10 yr) from Shanghai were enrolled in the study. Body composition was evaluated by bioelectrical impedance analysis (BIA). Activity energy expenditure (AEE) was estimated with a FitMate metabolic system (Cosmed, Rome, Italy).
Results: There were no differences in total AEE (kcal) between obese and lean children (boys: t = -1.422, p = 0.165; girls: t = 1.351, p = 0.203). The boys who were obese or overweight tend to have lower weight-adjusted AEE (kcal/kg/min) (t = 2.043, p = 0.051) and higher AEE (kcal/min) than lean boys (t = -2.910, p = 0.007); while the girls who were obese or overweight tend to have lower weight-adjusted AEE (kcal/kg/min) (t = 3.244, p = 0.003) and higher AEE(kcal/min) (t = -0.676, p = 0.504) than lean girls.
After controlling for age and gender, AEE(kcal/min) was significantly positively correlated (p < 0.05) with degree of obesity, FAT%, FM, FFM, FFMI in boys, while no statistical significance association was found between AEE(kcal/min) and the body composition (p > 0.05) in girls. There were negative correlation between weight-adjusted AEE (kcal/kg/min) and BMI, degree of obesity, FAT%, FM, FFM, FMI both in boys and girls (p < 0.05). In addition, no statistical significance association was found between weight-adjusted AEE (kcal/kg/min) and FFMI in boys(r-0.347, p
Conclusion: The hypothesis that obesity reduces AEE in children is partially supported. There are complex interactions among body size, body composition, and metabolic activity in children.
Obesity; children; energy expenditure; metabolism
∗119 A COMBINED PACKAGE OF MICRONUTRIENTS AND ALBENDAZOLE DOES NOT IMPROVE ENVIRONMENTAL ENTERIC DYSFUNCTION OR STUNTING IN RURAL MALAWIAN CHILDREN
Indi Trehan, Washington University in St. Louis, Saint Louis, MO, USA
Background: Environmental enteric dysfunction (EED) and linear growth stunting affect many rural agrarian children in the developing world and contribute to the persistently high rates of stunting that are observed worldwide. Effective interventions to improve EED are lacking.
Objective: We tested whether a package of interventions that included a single dose of albendazole, 14 days of zinc, and daily multiple micronutrient powder would decrease EED and stunting over 12–24 weeks in a cohort of rural Malawian children 12–23 months old.
Methods: This was a randomized, double-blind, placebo-controlled clinical trial with the primary outcomes being improvements in EED, as measured by the urinary lactulose-mannitol ratio from dual-sugar absorption testing, and linear growth. Outcomes were evaluated after 12 and 24 weeks of intervention, and compared to a placebo group.
Results: A total of 254 children were enrolled. After 12 weeks of study, children in the intervention group had an increase in their L:M ratio of 0.071 units, while children in the placebo group had an increase of 0.073 units (p
= 0.87). There was also no significant difference in L:M ratios at 24 weeks (increase of 0.088 units in the intervention group vs. increase of 0.080 units in the placebo group, p
= 0.19). Relative changes in length and weight also did not differ between the two groups.
Conclusion: The combined usage of a dose of albendazole, a course of zinc, and a daily multiple micronutrient powder did not decrease EED or stunting during the course of this study. Alternative interventions to improve these diseases should be investigated further.
120 AN ASSESSMENT OF THE ALVARADO SCORING SYSTEM IN THE DIAGNOSIS OF ACUTE APPENDICITIS AMONG THE PEDIATRIC PATIENTS AT A TERTIARY CARE MEDICAL CENTER
Ingrid G. Malaluan1, Juliet Sio-Aguilar2,1Kidapawan City, Philippines,2Philippine Pediatric Society, Quezon City, Philippines
Objectives: To review the demographics and clinical course of admitted patients, determine the Alvarado score of the surgically-confirmed cases and correlate the findings with histopathology results, correlate the Alvarado score and the results of the ancillary procedures, describe the alternative diagnoses of the patients initially considered to have an acute appendicitis and determine the negative appendectomy rate among patients who underwent operation.
Design: Retrospective, descriptive study.
Setting: St. Luke's Medical Center, Quezon City, a tertiary, private institution.
Participants: Eighty-two admitted pediatric patients from the emergency department assessed from January 1, 2012 to June 30, 2013 using the Alvarado score and suspected to have acute appendicitis were included in the study. Patients with imaging-confirmed diagnosis of appendicitis on arrival to the emergency department, those who were already treated conservatively with medications, patients with incomplete documentation, and those who were discharged against medical advice were excluded.
Main Outcome Measure: Histopathology findings among post-appendectomy patients and alternative diagnoses among those who were not operated on.
Results: There was a significant difference in the number of patients with scores 1–4, 5–6, and 7–10, with and without appendicitis, thus a significant correlation between the Alvarado score and the diagnosis of acute appendicitis existed. Among patients with acute appendicitis, there is an increasing trend of making accurate diagnosis with an increasing score group. Conversely, an opposite trend is observed among those without acute appendicitis. The negative appendectomy rate of this study was 10.6%.
Conclusion: The Alvarado scoring system is a helpful practical non-invasive diagnostic procedure that is simple, fast, cheap, safe, and reliable. It categorizes patients for discharge and for admission for further evaluation and management. Patents with score 7–10 should be admitted and undergo appendectomy to avoid complications. Patients with score 5–6 should also be admitted for close observation, who may require further studies to accurately make a diagnosis. Score 1–4 can be discharged with a general advice to seek medical attention as indicated.
Acute appendicitis, Alvarado score
121 SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS OF TREATMENTS FOR ACUTE DIARRHOEA AND GASTROENTERITIS IN CHILDREN.
Ivan D Florez1,2, Areti-Angeliki Veroniki3, Al-Khalifah, Reem4, Juan Yepes-Nunez1, Giordano Perez-Gaxiola5, Javier M. Sierra2, Carlos Cuello-Garcia1, Adriana M. Zea2, Robin Vernooij6, Jorge Acosta2, Gordon Guyatt1, Lehana Thabane1,1McMaster University, Hamilton, ON, Canada,2Universidad de Antioquia, Medellin, Antioquia, Colombia,3St Michael's Hospital, Toronto, ON, Canada,4King Saud University, Riyadh, Saudi Arabia,5Hospital Pediatrico de Sinaloa, Culiacan, Sinaloa, Mexico,6Iberoamerican Cochrane Centre, Barcelona, Spain
Background: Acute diarrhea and acute gastroenteritis (ADG) are common among children in low- and middle-income countries (LMIC) and high-income countries (HIC). Treatments for reducing the duration of ADG, in addition to oral rehydration, have been compared to placebo/standard treatment in randomized control trials (RCTs). They have shown some effect in reducing diarrhea against placebo/no-treatment (PLC/NT). Systematic reviews have synthesized some of these results showing that most of them are better than placebo. No summary of all the evidence is available to date. Our aim was to determine the comparative effectiveness of all available interventions for ADG in children and to describe the source and characteristics of the evidence across the world.
Methods: We conducted a systematic review of RCTs comparing zinc, vitamin A, probiotics (LGG, S. boulardii, and other strains), prebiotics, symbiotics, racecadotril, smectite, loperamide, fermented, diluted and lactose-free formula/milk, or its combinations, against them or standard treatment/placebo for reducing ADG treatment in children. Protocol registered at PROSPERO (CRD42015023778). We searched Medline, Embase, CINAHL, CENTRAL, Global-Health, LILACS, and grey literature. Review was performed in duplicate. We described the setting, types of comparisons, and results of effectiveness with descriptive statistics. We performed a Bayesian random-effects network metanalysis to determine the comparative effectiveness, and the effect estimates were calculated along with their credible intervals (95% CI). A ranking was performed to determine the best interventions. Quality of evidence was assessed with the GRADE approach.
Results: We screened 2898 studies; 156 proved eligible. In LMIC countries were performed 113 studies(72.4%). In total 124 studies (18,190 patients) measured diarrhea duration. Most of the trials compared a single intervention vs. placebo/no-treatment being the most common probiotics, zinc, and lactose-free (70.2%). Except for vitamin A, micronutrient mixtures, diluted milk and prebiotics, all the interventions were better than PLC/NT. Differences among the effective interventions ranged from a reduction of 14.92 to 38.4 hours, less than PLC/NT. Symbiotics (Mean Difference in hours: -29.10[-40.92; -17.19]) and S. boulardii+Zinc (-38.45 [-53.97; -22.70]) were the best-ranked interventions. Loperamide was the least safe. The GRADE quality of Evidence was Low and Very Low in most of the cases. Evidence of effectiveness of symbiotics was the one with the highest quality of evidence.
Conclusions: Evidence about treatments for reducing ADG duration comes mostly from comparisons: intervention vs. PLC/NT, and from LMICs. There is scant evidence directly comparing the interventions among them. Almost all the interventions were better than PLC/NT. However, differences among the interventions are small.
122 EPIDEMIOLOGY OF KAWASAKI DISEASE AND HENOCH-SCHÖLEIN PURPURA:14-YEAR SINGLE-CENTER EXPERIENCE
Jee Hyoung Yoo, Kee Hyuck Kim, Bong Sic Yun, NHIS Ilsan Hospital, Goyang, Gyeonggi-Do, Korea
Background: Kawasaki disease (KD) and Henoch–Schönlein purpura (HSP) are the two most common vasculitis in children. Although many nationwide epidemiology researches were performed, there was no study of regional epidemiology in certain areas in Korea. The purpose of this study was to evaluate the epidemiology of Kawasaki disease and Henoch–Schönlein purpura in the National Health Insurance Service (NHIS) Ilsan hospital, Goyang, Korea.
Methods: We retrospectively reviewed medical records of patients who were diagnosed with Kawasaki disease and Henoch–Schönlein purpura from March 2000 to February 2014 at the NHIS Ilsan Hospital in Goyang, Korea.
Result: The total cases of KD and HSP were 1202 and 623 patients over 14 years. The male-to-female ratio was 1.36:1 and 0.98:1, and mean age was 39.5 ± 29.7 months and 100.5 ± 54.1 months respectively. The annual numbers of KD patients changed from 45 in 2000 to 121 in 2013. The annual numbers of HSP patients were 35 in 2000 and the same in 2013. The monthly number for KD was slightly higher in summer (July) and winter (December),but the monthly number of HSP was lower in summer (August). The proportion of patients with KD among total inpatients and outpatients was 1.86% and 0.05%, and HSP was 0.45% and 0.06%, on average. Each inpatient and outpatient average annual growth rate of KD and HSP was 5% and 9% vs. -5% and -1%.
Conclusion: The number of Kawasaki disease patients and the proportion of the total number of patients in our institution was increasing, but the number and proportion of Henoch–Schönlein purpura patients has been gradually reduced. And, our epidemiology study of vasculitis in children is similar to that reported in previous nationwide studies in Korea.
123 EFFECTS ON FATTY ACID METABOLISM OF A NEW POWDERED HUMAN MILK FORTIFIER CONTAINING MEDIUM-CHAIN TRIACYLGLYCEROLS AND DOCOSAHEXAENOIC ACID IN PRETERM INFANTS
Claude Billeaud1, Carole Boué-Vaysse2, Leslie Couëdelo2, Philippe Steenhout3, Jonathan Jaeger3, Cristina Cruz-Hernandez3, Jacques Rigo4, Elie Saliba5, Jean-Charles Picaud6, Laurent Ameye7, Frédéric Destaillats7,1CIC Pédiatrique 1401 INSERM-CHU, Bordeaux, France,2Université de Bordeaux, Bordeaux, France,3Nestlé Health Sciences, Lausanne, Switzerland,4University of Liège, Liège, Belgium,5Hôpital Clocheville, CHU de Tours, Tours, France,6Hôpital de la Croix Rousse, Hospices Civils, Lyon, France,7Nestlé Nutrition R&D, Vevey, Switzerland
Background and Aims: In preterm infants, fortification of human milk (HM) with essential fatty acids (FA) is critical to support the high demands of growth. FA metabolism was investigated in preterm infants fed HM supplemented with a new fortifier (nHMF) that provided an additional intake of 0.76 g of medium-chain FA (MCFA), 58 mg of linoleic acid, 25 mg of alpha-linolenic acid (ALA), and 10 mg of docosahexaenoic acid (DHA) per kg/day to comply with the latest recommendations.
Methods: 153 preterm infants (birth weight ≤1500 g or gestational age ≤32 weeks) were randomized to receive HM fortified with nHMF or a lipid-free HMF. FA profile in plasma phospholipids, triacylglycerols (TAG), and red blood cell phosphatidylcholine and phosphatidylethanolamine (RBC-PE) were analyzed in a subgrouhalfNo of 40 infants before and after 21 days of feeding.
Results: Increased intake of MCFA in the nHMF group raised the levels of de novo synthesized palmitic acid and monounsaturated FA, possibly due to a larger available pool of acetyl-CoA resulting from dietary FA oxidation. ALA fortification in the nHMF group improved its incorporation in plasma TAG and the synthesis of eicosapentaenoic and docosapentaenoic acid. Similarly, additional DHA intake resulted in an increased DHA content in RBC-PE, which was not associated with a lower arachidonic acid content in this compartment as observed in plasma TAG and phospholipids. Numerous significant differences in FA levels were observed in RBC-PE (Table), a good indicator of FA metabolism and accretion.
Conclusions: HM fortification with nHMF efficiently supports FA anabolism and DHA accretion.
124 COW'S MILK PROTEIN ALLERGY IN INFANTS (CMPA). ENVIRONMENTAL FACTORS AS FACILITATORS OF DEVELOPMENT OF ALLERGY
María del Carmen Toca, Mirna Díaz, Patricia Carmen Sosa, Valeria Nivela, Carola Bayle, Silvia Morise, Gladys Mabel Convertini, Hospital Nacional A. Posadas, Morón, Buenos Aires, Argentina
Background: It is suggested that the neonatal intestinal microbiota is highly variable in its composition and depends on factors such as gestational age, mode of delivery, type of feeding, and environmental exposure. Intestinal microbiota has an important role in the postnatal development of the immune system and imbalances may lead to food allergies.
Aims: To analyze the association between the diagnosis of CMPA and the factors that could alter the intestinal microbiota in relation to perinatal record, personal history, environmental and/or pathological history.
Material and Methods: A retrospective descriptive study; 376 medical records of out-patient children, younger than 1 year, divided into two groupswere analyzed:
Group 1: Children diagnosed with CMPA, confirmed by controlled oral food challenge.
Group 2: Children without CMPA.
We analyzed mode of delivery, history of hospitalization, feeding, treatment with antibiotics (ATB) and episodes of gastroenteritis, before diagnosis of allergy in group 1, and during the first year of life in group 2.
Chi-square test and Mann-Whitney tests were used. It was considered significant, at p < 0.05.
Results: Group 1: Children with CMPA n = 182 Male: 54.4%
Group 2: Children without CMPA n = 194 Male: 47.9%
Children with CMPA were fed exclusively with breastfeeding 44%, with formula 43.4% and with breastfeeding and formula 12.6%. Children without CMPA: 62.9%, 3.1% and 34% respectively (p < 0.001).
Caesarean delivery increased the risk of CMPA, Odds ratio: 2,549 (95% CI 1.672- 3.884).
Conclusions: In this studied population, birth by Caesarean increased the risk of CMPA more than twice. Breastfeeding and vaginal delivery were protective factors.
The history of hospitalization, of treatment with ATB and episodes of gastroenteritis during the first year of life did not increase the allergy risk.
125 BRAZILIAN PAEDIATRICIANS’ APPROACH TO CHILDREN WITH GASTROESOPHAGEAL REFLUX SYMPTOMS
Sarah C Fontes Vieira1, Ricardo Queiroz Gurgel1, Flavia Mattos Gurgel2, Tiê Emidio Costa Silva2, Maria Zuleide Leão2, Ikaro Daniel de Carvalho Barreto3,1Federal University of Sergipe, Aracaju, Sergipe, Brazil,2Tiradentes University, Sergipe, Brazil,3Federal Rural University of Pernambuco, Brazil, Recife, Pernambuco, Brazil
Gastroesophageal Reflux (GER) is usually present in pediatric daily practice, with difficult management in some situations, which may involve pediatric gastroenterologist consultations. GER consists in the passage of gastric contents into the oesophagus that may occur as a physiologic process several times per day even in healthy infants and children. At 4 months old, up to 67% of the infants present regurgitation. However, only 2 to 3.3% are considered as Gastroesophageal Reflux Disease (GERD) and need intervention. Based on evidence of excessive GERD diagnosis and treatment, NASPGHAN and ESPGHAN jointly published a Pediatric Gastroesophageal Reflux Clinical Practice Guidelines in 2009 to provide a common resource for evaluation and management of infants and children with GER and GERD. This protocol remains as a reference nowadays all over the world. Quitadamo et al (2014) interviewed 567 European pediatricians to evaluate this guidelines implementation and observed that the majority was unaware of this protocol, frequently prescribing proton pump inhibitors (PPIs) despite a lack of efficacy for the symptoms being treated.
Objective: The aim of this study was to evaluate the current approach of Brazilian general pediatricians to children with GER symptoms, according to the NASPGHAN-ESPGHAN protocol.
Methods: Three hundred ninety randomly identified Brazilian general pediatricians were invited to ask a case report –structured questionnaire during 37th Brazilian Congress of Paediatrics in October, 2015. The Portuguese version of the European's twelve multiple choice case reports-like issues questionnaire, concerning the approach to infants, children and adolescents with symptoms suggestive of GER were presented to the pediatricians.
Results: None of the 390 interviewed pediatricians showed complete adherence (100%) to the guidelines. No difference in guidelines’ compliance was observed among the five regions of the country (p
= 0.774). Eleven percent of the respondents reported that usually request specific tests (upper gastrointestinal endoscopy and ph monitoring) and only 18.6% consider the child's age to establish diagnostic approach. Twenty-nine percent prescribe PPIs irrespective of child age; the majority of the pediatricians (59.5%) prescribe PPIs in infants with unexplained crying and/or distressed behaviour and 37.4% guide empiric trial of PPIs for all age children.
Conclusion: Although the 2009 NASPGHAN-ESPGHAN Guidelines recommendations aredisseminated all over the world and are the reference for GER/GERD management, Brazilian pediatricians’ practice generally diverges from this document. PPI prescription is high despite a lack of efficacy on the symptoms being treated.
127 EFFECTS OF MATERNAL NUTRITION ON QUANTITY AND NUTRITIONAL QUALITY OF BREAST MILK: SYSTEMATIC REVIEW
Trudy Voortman1, Audry H. Garcia1, Kim V.E. Braun1, Sagar K. Thakkar2, Myrte J. Tielemans1, Wendy Stroobant3, Gisella Mutungi2, Wichor M. Bramer1, Josje D. Schoufour1, Francesa Giuffrida2, Irma Silva-Zolezzi2, Oscar H. Franco1,1Erasmus MC, University Medical Center, Rotterdam, Netherlands,2Nestlé Research Center, Lausanne, Switzerland,3VU University, Amsterdam, Netherlands
Background and Objectives: Breastfeeding is considered infant nutrition's gold standard. However, the composition of breast milk varies according to the stage of lactation, time of day and between mothers. The role of maternal nutrition in breast milk quantity and content is of great importance to understand because of its potential for intervention. Consequently, we systematically reviewed the literature on the effects of diet, supplement use, and nutrient status on nutritional quality and quantity of breast milk.
Methods: Eight electronic databases were searched (up to February 2015) for interventional and observational studies that reported associations between nutrient blood levels, food or nutrient intake, dietary patterns, or dietary supplement use during pre-pregnancy (up to 6 months before conception), pregnancy, or lactation with nutritional quality or quantity of breast milk. Study selection was performed by two independent investigators.
Results: We identified 6198 unique references and retrieved full-texts for 814 articles, of which 370 met all selection criteria. Many of the included studies focused on breast milk levels of fatty acids (93 studies), vitamin A or carotenoids (63 studies), B vitamins (50 studies), zinc (44 studies), iron (31 studies), and calcium (22 studies). Overall, high-quality research on the effect of nutrition on breast milk production is scarce, and evidence for effects on energy content or macronutrient composition is inconsistent. However, there is strong evidence for effects of intake of omega-3 polyunsaturated fatty acids on its concentrations in breast milk. For micronutrients, there is moderate to strong evidence that dietary intake and blood levels of iodine, selenium, vitamin A, certain B vitamins (e.g., thiamine, riboflavin, choline, vitamin B12), vitamin C, vitamin D, and vitamin K are associated with their respective levels in breast milk. Evidence for an effect of maternal nutrition on breast milk iron, zinc, and vitamin E is inconclusive; and evidence for chromium, fluoride, sodium, potassium and other minerals is scarce. Tthe current evidence supports no effect of dietary intake or blood levels of calcium, magnesium, or copper on their concentration in breast milk.
Conclusions: The literature to date suggests an effect of maternal nutrition on breast milk quality. Breast milk levels of several nutrients that are important for infant growth and development, such as polyunsaturated fatty acids, iodine, selenium and vitamins A, B, C and D, depend on adequate maternal nutrition, whereas concentrations of calcium, magnesium and copper in breast milk are not affected by maternal nutrition. More research is needed on the effects of maternal nutrition on breast milk content of iron, fluoride, potassium, zinc, chromium, sodium, and vitamin E and on breast milk quantity.
128 IMPACT OF MEDICAL AND NUTRITIONAL MANAGEMENT IN PATIENTS WITH FOOD ALLERGIES IN A GASTROENTEROLOGY, HEPATOLOGY, AND NUTRITION REFERENCE CENTER OF COLOMBIA (2008 - 2014)
Wilson Daza Carreño, Silvana Dadan, Ana Maria Rojas, Gastronutriped, Bogota, Cundinamarca, Colombia
Introduction: In the Colombian pediatric population, as has as well been reported in the literature worldwide, an increase in food allergy (FA) has been observed. In our experience, a significant proportion of these patients have been diagnosed as having some degree of compromise of their nutritional status. Therefore, early diagnosis and an appropriate interdisciplinary approach would favor the window of opportunity for growth.
Objective: To evaluate the impact of medical-nutritional treatment on the growth of patients diagnosed with FA in the first two years of life in a gastroenterology, hepatology, and nutrition reference unit between 2008 and 2014.
Materials and Methods: Retrospective cohort study. Patients aged 0 to 2 years old, who had been diagnosed with FA and who had completed medical-nutritional treatment, were included. The data were extracted from medical records. A descriptive analysis was made. Nominal and ordinal categorical variables were summarized with distributions of absolute and relative frequencies. For continuous variables, measures of central tendency and dispersion measures were used. The assumption of normality was validated using the Shapiro-Wilks test (quantitative variables). To determine differences between groups, Student's t-test was used. p < 0.05 was considered statistically significant in a single queue. Nutritional status was defined by anthropometric indicators using WHO Anthro software. The frequency of each WAZ, HEZ, and WHZ indicator was estimated at the beginning of the treatment and at the food challenge. To determine the changes in physical growth parameters, Student's t-test was used for related data, prior to assessment of equal variances. p < 0.05 in a single queue was considered statistically significant at.
Results: The sample consisted of 50 patients. There were increases in median weight (460 g; RIC 340–608 g), in length (1.9 cm; RIC 1.6 to 2.5 cm), and in head circumference (0.7 cm; RIC 0.5 - 0.7 cm) for each consultation attended by the patients. The WAZ media was -1.15 (95% CI,-1.50, -1.80) at the start of treatment and -0.39 (95% CI, -0.65, -0.12) at completion, with p < 0.0001. The HAZ was -1.60 (95% CI, -1.99, -1.21) when starting treatment and -0.98 (95% CI, -1.32, 0.65) at the end thereof, with 0.001 p. WHZ was 0.06 (95% CI -0.29, 0.43) at the beginning and 0.11 (95% CI, -0.17, 0.41) after the treatment, with no significant difference.
Conclusions: In patients with FA, statistically significant differences for WAZ and HAZ indicators before and after the medical-nutritional treatment were found. The negative effect on weight and height of some children with FA could improve with a proper approach between pediatric nutrition and gastroenterology.
129 PRESCRIPTION TENDENCY OF GASTRIC ACID SUPPRESSANTS IN HOSPITALIZED CHILDREN IN A UNIVERSITY HOSPITAL
Lady Katherine Mejia-Perez1, Jose Fernando Vera Chamorro2, Marianna Puccini Dicolloredo Mels2, Johan Sebastián Zambrano Salamanca2,1Mayo Clinic, Jacksonville, FL, USA,2Hospital Universitario Fundacion Santa Fe de Bogota, Bogotá, Bogotá D.C., Colombia
Background: There is over-prescription of proton-pump inhibitors (PPIs) and H2-blocker receptors (H2B) in the inpatient pediatric population. Acid suppressive therapy in hospitalized children has been associated with adverse events such as acute gastroenteritis and pneumonia, resulting in increased days of hospital stay, and augmented costs to the healthcare system. Furthermore, there are no international guidelines regarding the appropriate PPI and H2B use in hospitalized pediatric patients.
Methods: Retrospective cross-sectional study. Patients between 1 and 15 years old, who were hospitalized between January 1t, 2013 and December 31, 2013, and received PPIs and/or H2B, were included. Demographic information, the drug used, its indication, dose, administration route and length of therapy were abstracted by retrospective chart review. Guidelines for the appropriate use of PPIs and H2B in pediatric inpatient population were proposed, based on the current guidelines available for adults. The collected prescription indications were evaluated by use of the proposed guidelines, in order to determine whether an indication was appropriate or not.
Results: 67 patients were included (mean age 6.9 years, SD 4.6, 55.2% male). 24 patients (38.5%) met the proposed criteria for prescription of gastric acid suppressants in hospitalized children. Intravenous ranitidine was used in 66 (98,5%) patients. The most frequent correct indications were gastroesophageal reflux disease in 8 (12%) and prevention of bleeding associated with stress in 8 (12%). The mean length of stay and length of acid suppressive therapy were 5.1 and 4.8 days, respectively. The most common unaccepted, but prophylactic indication was their use in vomiting and acute gastroenteritis.
Conclusions: PPIs and H2B prescription patterns do not met the proposed indications for pediatric inpatients, resulting in over-prescription in the pediatric inpatient section of a university hospital.
130 HYPOVITAMINOSIS D IN PEDIATRIC AND PREGNANT POPULATIONS IN A UNIVERSITY HOSPITAL
Karen Guisselle Olivar Carreño1, Jose Fernando Vera Chamorro1, Aldemar Mejía Botello1, Ana Margarita Baldión Elorza2, Oscar Alberto Bernal Acevedo1, Byron Cardoso Medina2, Claudia Marcela Pérez Ramírez2,1Escuela de Gobierno. Universidad de Los Andes; PediAFe Research Group, Bogotá, D.C., Columbia,2Hospital Universitario Fundación Santa Fe de Bogotá, Bogotá, D.C., Colombia
Introduction: Vitamin D deficit is a public and global health problem. In Colombia and Latinamerica, there are few reports available on the prevalence of hypovitaminosis D in neonatal and pregnant populations. Although in equatorial countries it is assumed that constant UVB exposure potentially prevents vitamin D deficiency, a prevalence of hipovitaminosis D of 9%-83% and 30–96% has been reported for pregnant women and newborns, respectively. We prospectively evaluated hipovitaminosis D prevalence in newborns and their mothers.
Methods: A prevalence study was conducted. Pregnant women who underwent labor in Hospital Universitario Fundación Santa Fe de Bogotá (HU-FSFB), Bogotá, Colombia, from October 2015 to January 2016 were included. Maternal and cord blood samples were obtained during labor. Peripheral blood samples were obtained from newborns with low vitamin D levels demonstrated on umbilical cord blood samples. Quantitative determination of 25-hydroxivitamin D levels was performed by use of the chemioluminescent microparticle immunoassay, Architet 25 OH Vitamin D assay®. Vitamin D status was classified as sufficiency if 25 OH vitamin D levels ≥30 ng/mL, as insufficiency if <30 ng/mL or ≥20, and as deficiency if <20 ng/mL.
Results: 85 pregnant women and 86 newborns were evaluated (1 twin pregnancy). 60 (69.7%) mothers and 74 (86%) newborns were found to have vitamin D deficit. The prevalence of vitamin D deficiency was 24 (27.9%) and 30 (34.8%), of insufficiency it was 36 (41.8%) and 44 (51.2%), and of sufficiency it was 26 (30.2%) and 12 (13.9%), for mothers and newborns, respectively. Peripheral confirmation was performed in 45 newborns: medium value of 17,6 ng/mL (± 5.42 SD). 32 (71.1%) demonstrated deficiency (initial classification: deficiency 17 (53.1%), insufficiency 15 (46.9%) and 13 (28,9%) demonstrated insufficiency (initial classification: deficiency 1 (7,7%), insufficiency 12 (92.3%).
Conclusion: Vitamin D deficiency is a highly prevalent condition in both maternal and newborn populations. Studies to assess its prevalence in other areas the risk factors should be performed. Routine measurement of vitamin D levels and its appropriate substitution during pregnancy and the neonatal period are encouraged. Cuantification of Vitamin D levels in umbilical cord blood samples is a sensitive but unspecific test to identify hypovitaminosis D.
148 LONG-TERM (MORE THAN 10 YEARS) OUTCOME OF LIVER TRANSPLANTED CHILDREN
Ba Abou, Fernando Alvarez, Massimilano Paganelli, Devendra Amre, Sainte Justine University Hospital Center, Montreal, QC, Canada
Liver transplantation (LT) is an effective treatment for a varietyof irreversible liver diseases for which there is no other satisfactory therapy, as well as for cases in which late diagnosis precludes other therapeutic options. The progress of surgical techniques and the monitoring of the complications had improved the long-term survival of patient with end-stage liver disease. Nevertheless, the long-term outcome of patients receiving liver transplantation during the pediatric age is not yet well described.
Aim: The aim of this study is analyse the long-term outcome of liver transplanted children having survived 10 years or more from liver transplantation.
Methods: The medical records of 108 patients younger than 18 years of age undergoing liver transplantation for end-stage liver disease from March 31, 1986 to December 31, 2005 were reviewed retrospectively. Actuarial patient and graft survival rates where determined at 10 and 20 years. The etiology of the liver disease and incidence of post-transplantation complications were determined.
Results: A total of 106 patients underwent 116 LTs. Seven (6.6%) out of the 106 patients died, but only 1 after 10 years of follow-up. Therefore, 99 (93.40%) patients are alive >10 years post liver transplantation,of whom53 (53.53%) survived for 20 years or more. The male sex represented 51.51% of the cohort. Biliary atresia 32 (32.32%) and tyrosinemia 26 (26.26%) were the most common causes (58.58%) of end-stage liver disease in our population. The median recipient age was 3.58 years. All grafts (55.14% reduced livers, 44.85% whole organs) were from deceased donors. The median age of donor was 31 years. Four patients (4.04%) required retransplantation after ten years. On average, 0.6 late acute rejections (after 1 year post-transplant) per patient were registered. Overall, 23.23% of patients showed signs of chronic hepatitis at liver biopsy between 10 and 30 years of follow-up, and 18.18% presented liver cirrhosis. One patient developed cirrhosis due to chronic hepatitis E virus infection. Epstein Barr virus primary infection was seen in 16 patients. One patient developed post-transplant lymphoproliferative disease. At last follow-up, the mean alanine aminotransferases was 31 U/L(12–982) and bilirubin at 14.8 μmol/L (4–765). The synthetic liver function was normal in all patients. Portal thrombosis was the only vascular complication seen in 6 patients (6.06%). The renal function was normal with glomerular filtration rate above 120 cc/min/1.73cm3. For metabolic screening, the median of BMI is 24.32 and only 1 patient developed type 2 diabetes.
Conclusion: Patient and graft survival, as well as liver function, are excellent in the long-term follow-up of liver transplanted children. The most frequent complication in the studied period is the development of chronic hepatitis (supposedly secondary to immune-mediated hepatocyte rejection).
149 MARKERS OF SLEEP-DISORDERED BREATHING AND METABOLIC RISK FACTORS IN PEDIATRIC NON-ALCOHOLIC FATTY LIVER DISEASE
Alisha Jamal, Marialena Mouzaki, Saadoun Bin- Hasan, Indra Narang, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
Objective: To determine whether markers of sleep-disordered breathing, other than obstructive sleep apnea, are associated with markers of liver injury and metabolic risk factors in pediatric non-alcoholic fatty liver disease (NAFLD).
Methods: Retrospective chart review of pediatric patients with NAFLD followed at the Hospital for Sick Children. Children ages 2–18 with NAFLD were included. Demographic, clinical, laboratory and polysomnography data were collected. Subjects were divided into groups based on: a) obstructive apnea hypopnea index (OAHI) ≥ or <5 events/h; b) Desaturation index (DI) ≥6 or <6 events/h and 3) Arousal Index (AI) ≥14 vs. <14 events/h. Markers of liver disease severity were compared between groups using Mann-Whitney or Student's t-test, as appropriate.
Results: Thirty children (70% male) were included in the study. Mean age (±SD) was 13 ± 4 years and mean BMI z score 2.4 ± 0.9. There was no difference in serum levels of ALT (91 vs. 112 U/L, p = 0.52), AST (8.2 vs. 16.4 U/L, p = 0.64), alkaline phosphatase (ALP, 28.3 vs. 33.6 U/L, p = 0.84) and GGT (6.6 vs. 8.4 U/L, p = 0.73) between those with a low and a high OAHI. In addition, there was no difference between the groups in BMI z score (2.2 vs. 2.7, p = 0.18); HbA1c (5.6% vs. 5.5%, p = 0.50); fasting glucose (5.1 vs. 5.0 mmol/L, p = 0.77), insulin (111 vs. 132 pmol/L, p = 0.40), triglyceride (TG, 1.4 vs. 1.6 mmol/L, p = 0.66), LDL cholesterol (2.3 vs. 2.9 mmol/L, p = 0.19), HDL cholesterol (mean 1.1 vs. 1.2 mmol/L, p = 0.36), and total cholesterol (mean 4.1 vs. 4.8 mmol/L, p = 0.16). When dividing the cohort using the DI threshold, there was no difference between the groups in ALT (23 vs. 16 U/L, p = 0.27), AST (63 vs. 43 U/L, p = 0.24), ALP (206 vs. 215 U/L, p 0.85), and GGT (43 vs. 39 U/L, p = 0.67). Further, there was no difference in BMI z score (2.2 vs. 2.9, p = 0.06); HbA1c (mean 5.6 vs. 5.4%, p = 0.60); fasting glucose (5.2 vs. 4.9 mmol/L, p = 0.47), insulin (117.3 vs. 110.1 pmol/L, p = 0.79), TG (1.4 vs. 1.5 mmol/L, p = 0.88), LDL (2.3 vs. 2.8 mmol/L, p = 0.23), HDL (1.2 vs. 1.1 mmol/L, p = 0.55) and total cholesterol levels (4.1 vs. 4.6 mmol/L, p = 0.33). Finally, we determined if there was a relationship between AI and the above parameters. Again, there were no differences in ALT (94 vs. 103 U/L, p = 0.80), AST (54 vs. 58 U/L, p = 0.80), ALP (236 vs. 186 U/L, p = 0.25), and GGT (47.1 vs. 38.1 U/L, p = 0.40), nor in any metabolic parameters: BMI z score (2.2 vs. 2.6, p = 0.29), HbA1c (5.5 vs. 5.5%, p = 0.94), fasting glucose (5.2 vs. 4.9 mmol/L, p = 0.45), insulin (113 vs. 122 pmol/L, p = 0.68), TG (1.6 vs. 1.4 mmol/L, p = 0.42), LDL (2.4 vs. 2.7 mmol/L, p = 0.48), HDL (1.1 vs. 1.2 mmol/L, p = 0.57), and total cholesterol levels (4.2 vs. 3.5 mmol/L, p = 0.55).
Conclusion: This study did not find associations between markers of sleep-disordered breathing and evidence of liver injury or metabolic factors in children with NAFLD. Further studies to assess the impact of sleep-disordered breathing on NAFLD are needed.
150 OUTCOME OF NON-PHARMACOLOGICAL MANAGEMENT OF NON-ALCOHOLIC FATTY LIVER DISEASE IN HISPANIC VS. NON-HISPANIC CHILDREN
Baraa Alabd Alrazzak, Pratik Patel, Essam Imseis, University of Texas - Health Science at Houston, TX, USA
Introduction: Non-alcoholic fatty liver disease (NAFLD) is a slowly progressive disorder of fat accumulation within hepatocytes with gradual development of inflammation, focal necrosis, and in many cases, fibrosis. It is the most common liver disease in the United States, particularly in those who are of Hispanic descent, male gender, and/or obese.
The pathophysiology of NAFLD is poorly understood but is much more prevalent in obese individuals. A number of events may precipitate the injury associated with this disorder. Insulin resistance is often described as the “first hit” or injury that predisposes and individual to NAFLD. This can lead to alterations in hepatic fat metabolism and accumulation of lipid droplets within the hepatocytes. Oxidative stress or a 'second hit’ is required to develop inflammation and fibrosis, and diet, environment, drugs, and toxins are believed to be a source of this stress.
Purpose: To determine the outcome of NAFLD using non-pharmacological management including lifestyle modification involving daily exercise and dietary modification in Hispanic versus non-Hispanic children.
Methods: A retrospective study of individuals younger than 19 years. Information regarding gender, ethnicity, age at diagnosis, BMI, family history of liver disease, and other comorbidities were collected.
Data collected included BMI%ile, Z-score for weight, ALT, AST, GGT, liver biopsies, and liver ultrasounds, which were obtained at the time of diagnosis and after 6- 9 months of lifestyle modification. The patients were divided into two groups: Hispanic and non-Hispanic. Outcome was improvement of BMI Z- scores, AST and ALT at the end of 9 months.
Results: A total of 42 patients with NAFLD were included to date in the study;,of which30 were Hispanic. All patients were evaluated by the same hepatologist and received the same counseling regarding lifestyle modification. Median age at diagnosis was 10 and 11.6 years respectively. Median ALT level at time of diagnosis was 121 unit/liter in the Hispanic group and 225 unit/liter in the non-Hispanic. After 9 months of non-pharmacologic management; 66% of patients in the non-Hispanic group had a normal ALT level, and 16% showed improvement without normal ALT levels. On the other hand in the Hispanic group, only 7% of patients had normal ALT at the end of 9 months, 33% had improvement of ALT, while 50% had worsening of the ALT. (p 0.001). Table1.
Conclusion: Nonpharmacologic management with lifestyle modification resulted in limited improvement in Hispanic patients with NAFLD, in comparison to non-Hispanic patients. While compliance may play a major role in patient outcome, differences in outcome in Hispanic and non-Hispanic children may suggest some other underlying genetic modifiers. Also, the low rates of improvement in children with intensive lifestyle modification suggests a strong need for other therapeutic strategies for management of this disease.
151 CARBOHYDRATE-RESTRICTED DIET LOWERS HEPATIC TRIGLYCERIDE IN OBESE ADOLESCENTS WITH METABOLIC SYNDROME AND NON-ALCOHOLIC FATTY LIVER DISEASE
Charina M. Ramirez1, Jennifer A. Panganiban2, Niviann Blondet1, Julia Kozlitina1, Rachel Barraco3, Christopher Flores3, Lily Iteld3, Stevie Puckett3, Norberto Rodriguez-Baez1, Jeffrey D. Browning1,1University of Texas Southwestern Medical Center, Dallas, TX, USA,2Children's Hospital of Philadelphia, Philadelphia, PA, USA,3Children's Medical Center, Dallas, TX, USA
Background: Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in children. Obesity, insulin resistance and metabolic syndrome (Met-S) are strongly associated with NAFLD. The pathophysiology of NAFLD indicates that the presence of excess triglycerides (TG) in liver is an absolute requirement for disease progression to occur. TG is derived primarily from peripheral lipolysis as well as lipid synthesis from carbohydrate (CHO) precursors in liver. While decreasing adiposity is the mainstay of therapy, data in adults have shown that dietary carbohydrate restriction is more effective in reducing hepatic TG content than calorie restriction. To date, the effectiveness of carbohydrate restriction on pediatric NAFLD has not been studied.
Objective: The aim of this study is to determine whether a 6-month dietary carbohydrate-restriction is superior to calorie-restriction in reducing hepatic TG content in children with biopsy proven NAFLD and Met-S.
Methods: Nineteen subjects with Met-S and NAFLD (14 male and 5 female) ages 11–17 years were enrolled and randomized to either a carbohydrate–restricted diet (20% carbohydrates, 35% protein and 45% fat) or calorie-restricted diet (50% carbohydrate, 15–20% protein and 30–35% fat) for 6 months. Hepatic proton magnetic resonance spectroscopy (1H-MRS) and serologic testing were obtained at baseline, after 2 months and after 6 months of dietary intervention.
Results: There was no difference between the carbohydrate–restricted and calorie-restricted group in BMI z-score change from baseline to 2 months or 6 months post-intervention. Hepatic TG decreased significantly more in carbohydrate–restricted subjects (mean ± SD, -26.80 ± 17.60%, -31.61 ± 25.95% at 2 months and 6 months, respectively) than in calorie-restricted subjects (3.80 ± 20.18%, 19.38 ± 28.01%). The plasma alanine aminotransferase (ALT) level was also significantly reduced in carbohydrate–restricted subjects compared to calorie-restricted subjects (p < 0.05 at 2 months and p = 0.004 at 6 months).
Conclusions: This preliminary study shows that a carbohydrate–restricted diet effectively reduces hepatic TG and ALT in obese adolescents with NAFLD and Met-S.
152 NEONATAL LIVER FAILURE DUE TO HERPES SIMPLEX VIRUS INFECTION: A TERTIARY LIVER CENTRE EXPERIENCE
Chaya Kelgeri, Gupte, Patrick Mckiernan, Indra Van Mourik, Deirdre Kelly, Jane Hartley, Khalid Sharif, Darius Mirza, Birmingham Children's Hospital NHS Trust, Birmingham, UK
Introduction: Neonatal liver failure (NLF) though rare is a life-threatening condition. Liver transplants (LTx) have made a substantial improvement to the mortality and morbidity rates in this group of patients. Infections contribute to a sizeable cause of NLF and Herpes simplex (HSV) infection is the commonest viral infection.
Aim: To report the incidence of NLF due to HSV and their outcome at a national pediatric liver transplant centre 1991-2014.
Methods: Retrospective analysis of liver unit data and medical notes of neonates admitted with acute liver failure. NALF was defined as age <28 days, admitted with acute liver failure (PT>15 or INR>2 not correctable by Vitamin K) between 1991 to 2014. The primary outcome measure in NLF was survival without transplantation, death or transplantation.
Results: 133 neonates with NLF were identified between 1991–2014. All babies were transferred from other hospitals. The other etiologies included Galactosemia (n = 29, 21.8%), neonatal haemochromatosis (n = 26, 19.5%), mitochondrial causes (n = 10, 7%), HLH (n = 4,3%), metabolic conditions (n = 8, 6%) and infections (n = 25,18.7%). In 31 babies (16.5%), the cause was indeterminate. The infectious group was predominated by the viruses (n = 21), Herpes simplex group being the most common (n = 16, 12%). Of the 16 babies with HSVneonatal failure, 7 were girls and 9 boys. All babies were term except two being premature at 34 and 36 weeks. History of genital lesions was present in only two mothers. The median age of presentation was 9 days (2–21 days). All babies presented with signs of sepsis and only 4 babies had vesicles on clinical examination. Surface swabs were positive in 9 and blood PCR in 12 babies. HSV was type 1 in 7 babies and type 2 in 6. 3 babies did not have the type documented. The median Prothrombin time was 45 secs (18–120). Al. 10 babies required multi-organ support in form of ventilation, inotropes and renal replacement therapy and of these only 4 survived. The total survivors in this cohort were 6, 5 -medical treatment and one- transplant. 10 babies died (2 on the waiting list for liver transplant, 2 after LTx and 6 on medical management). All babies who died, including the ones after LTx, were receiving multi-organ support. The two neonates transplanted at 12 days (weight 3.5 kg) and 20 days (wt 3.4 kg) died at 3 days and 43 days respectively. The only neonate surviving after LTx was transplanted at 15 days of age, weighing 2.5 kg. One baby was listed for transplant but suspended due to multi-organ failure (MOF) but then went on to improve with medical support and eventually recovered without a LTx.
Conclusion: Herpes simplex virus infection is a common cause of NLF. Early referral, early start of acyclovir and prompt management of intensive care should be instituted in these children as progression to multi-organ failure is rapid. LTx can be offered to a select sub-group of children with isolated liver failure who recovered from MOF.
153 PEDIATRIC LIVING-RELATED LIVER TRANSPLANTATION-EXPERIENCE IN CENTRAL TAIWAN
Chieh-Chung Lin1, Shao-Ju Lin2, Shou-Bin Tzeng1,1Taichung Veterans General Hospital, Taichung, Taiwan,2Show Chwan Memorial Hospital, Taichung, Taiwan,
Background: Pediatric living-related liver transplantation (LRLT) is widely accepted as treatment for children with endstage liver disease and acute liver failure. The pediatric LRLT program was started in 2006 in Taichung Veterans General Hospital, the only LTx medical center in central Taiwan. We aimed to review the outcome and complications of LRLT of our program.
Method: We reviewed children who received LRLT between January 2006 and December2014. Charts were reviewed including patient characteristics, transplantation indication, operation method and the graft selection. The main outcomes were 5-year survival of patients, and graft and the complications after LRLT.
Result: Within the study period, twenty-five children (12 boys and 13 girls) received LRLT. The age was between 5 months to 17 years old. The median age was 1year, 5 months. There were 8 patients under one year of age (32%). For patient with biliary atresia(17, 68%), the main indication for LRLT was advanced cirrhosis with portal hypertension, with or without GI bleeding. Recurrent cholangitis also contributed to transplantation. The other etiologies(8. 32%) included acute fulminant hepatitis (3), Wilson's disease (1), autoimmune hepatitis (1), Allagille's syndrome (1), Budd-Chiari syndrome (1) and idiopathic liver cirrhosis (1). The donor liver segment was chosen according to the size of recipient (left lateral segment: 12; left lobe: 11; right lobe: 2). Five patients expired during follow-up (20%). The causes of mortality included H1N1 infection, PTLD, recurrent autoimmune hepatitis, sepsis and subdural hemorrhage each. No re-transplantation was performed after LRLT. Five-year patient and graft survival rate were both 79.5% calculated by Kaplan-Meier survival analysis. For patients under one year of age, the 5-year survival rate was 85.7% (7/8). For patients older than one year, the 5-year survival rate was 76.5% (13/17). Operative complications included hepatic vein stenosis (1), portal hypertension (3), biliary complication (7). Infection was defined as patient with fever response to antibiotic treatment or positive bacterial culture. Seventeen patients (68%) had at least one episode of infection after LRLT. Seven patients (28%) had acute rejection (early or late). De novo HBV infection occurred in 3 patients after LRLT. ABO incompatibility LRLT was done in a 10-month-oldfemale with biliary atresia who survived for more than 7 years to the present.
Conclusion: Biliary atresia is the most common underlying disease in our series in children who need LTx. The survival rate of patients less than one year of age had relatively good outcome compared to older ages in our study. Complications and mortality might occur after LTx that need careful management for the best results. ABO incompatibility LTx remains a choice of pediatric LRLT as needed.
154 TENDER HEPATOMEGALY AND ABNORMAL PATTERN OF HEPATIC STEATOSIS IN NON-COMPLIANT ADOLESCENTS WITH POORLY CONTROLLED TYPE 1 DIABETES MELLITUS
Chrissy Lopez, Nitika Gupta, Andrew Muir, Carlos Abramowsky, Jay Freeman, Miriam Vos, Dellys Soler, Saul Karpen, Renée Romero, Children's Healthcare of Atlanta, Emory University, Atlanta, GA, USA
Background: Glycogenic hepatopathy (GH) is an under-diagnosed condition in adolescents with poorly controlled Type 1 diabetes mellitus (T1DM). Though Mauriac syndrome has been described as a complication of T1DM and characterized by growth retardation, delayed puberty, and cushingoid facies, most patients do not present with these classic features. In this study we describe clinical-pathologic characteristics, which are unique and specific to this condition in adolescents with poorly controlled T1DM.
Methods: Patients with known DM1 who were found to have hepatomegaly or elevated liver function tests were referred to hepatology services at a single, large, tertiary care institution over a period of 18 months. Initial evaluation included screening for common liver disorders, imaging and liver biopsy. Patient characteristics including age at diagnosis of diabetes, HbA1C levels, age at diagnosis of liver dysfunction or hepatomegaly, glycemic control and compliance were noted.
Results: Of the 19 patients with Type 1 diabetes mellitus and hepatic involvement, there was a female predominance (15:4), with median age of 15 (11–19) years and normal BMI at presentation. Median age at diagnosis of diabetes mellitus was 9 (1–16) years. Hepatomegaly was noted in 18/20 and was the reason for referral; with 2/20 being referred for elevated LFTs. Half (9/18) had developed acute tender liver enlargement requiring an unscheduled visit to the clinic or Emergency room. The median age at liver presentation was 15 (11–19) years. Patients with hepatic involvement demonstrated poor glycemic control with a median HbA1C of 12.4 (7.6–14.2) % and reported non-compliance with insulin regimen. Liver enzymes varied widely, ranging from 21–1461 IU/l (AST) and 17–564 IU/l (ALT) at the time of diagnosis of hepatomegaly, which was confirmed in all patients by imaging. Interestingly, hepatomegaly showed a dramatic decrease with resolution of abdominal pain with improvement in blood sugar even in the absence of a detectable change in HbA1C. Ten patients had a liver biopsy, which showed abnormal presence and pattern of steatosis with perisinusoidal deposition of fat, which was unusual and distinct from fatty liver seen in metabolic syndrome. Though glycogen deposition was also seen, it did not show any distinct characteristics.
Conclusion: Poorly controlled T1DM in non-compliant adolescents can lead to liver dysfunction presenting with acute onset of tender hepatomegaly and elevated LFTs, which improve with glycemic control. Presence of perisinusoidal fat in the liver likely represents an as-yet unidentified mechanism of development of hepatic dysfunction in T1DM requiring further investigation.
155 LIVER INTERVENTIONAL RADIOLOGY IN CHILDREN: A 20 YEAR EXPERIENCE
Cristina Gonçalves, Sandra Ferreira, Susana Nobre, Paulo Donato, Alfredo Gil Agostinho, Vitor Carvalheiro, Isabel Gonçalves, Emanuel Furtado, Coimbra University and Hospital Centre, Coimbra, Portugal
Background: Diagnostic and therapeutic management of liver disease, and in particular in recipients of liver transplants, includes the use of interventional radiology procedures. Although challenging, the use of this technique in children is an emerging field and provides a large number of possibilities for diagnosis and/or therapeutics of liver disease.
Aim: The authors report the interventional radiology experience in children and the changes in type of procedures performed over two decades in an adult facility care associated with a liver transplantation centre.
Methods: Descriptive analysis of interventional radiology procedures performed in a twenty-year period (October 1995 to December 2015) in children (<18 years) with liver disease. All patients were admitted.
Demographic features, weight, type of procedure, previous liver transplantation (LT), time since LT, success of the procedures, complications and mortality were recorded and analyzed. The variation of the type of procedures performed over time in four periods (1995–2000; 2001–2005; 2006–2010; 2011–2015) was also assessed.
Results: 101 procedures were performed in 59 patients (median 1 procedure/ patient (1–5)); 51% (30) males; median age: 9 years (7M-16Y); median weight: 28 Kg (4,6–70); Type of procedure: 31 abdominal selective angiography (SAA); 11 cavography, 31 percutaneous colangiography (PCT), 10 direct portography (DP), 8 TIPS placement; 10 combined procedures (8 SAA + cavography; 1 DP + PCT; 1 SAA + DP).
81 patients (80%) had previous LT. Median time between LT and procedure was 185 days (1–3369 days). In 75% procedures, there was therapeutic intervention.
There were complications in 17% (17) of procedures: 2 major complications: hypovolemic shock (2); 15 minor: fever (4), gastrointestinal bleeding (3), endotoxemia (2), small hematoma (2), cholangitis (1), catheter fracture (1), local pain (1), biliary leak (1). No patient died from a procedure. Intervention was successful in 64% (65). In the period 1995 to2000, 19 procedures were performed (10 PCT; 4 cavography; 3 SAA; 2 DP); from 2001 to 2005, there were 14 procedures (8 SAA; 2 PCT; 2 DP; 1 cavography; 1 SAA + cavography); in the period 2006–2010, 28 procedures were performed (9 SAA; 9 PCT; 4 SAA + cavography; 4 cavography;1 DP + PCT; 1 DP) and from 2011 to 2015, there were 40 procedures (11 SAA; 10 PCT; 3 ASA + cavography; 5 DP; 2 cavography; 8 TIPS placement; 1 ASA + DP).
Discussion: The great majority of interventional radiology procedures were performed in children previously submitted to LT. We highlight the high rate of therapeutic interventional procedures in this series, such as the low prevalence of major complications. The number of procedures has been growing over the years, and the types of procedures have also been changing, currently including complex procedures such as TIPS placement.
156 LONG TERM DEVELOPMENTAL OUTCOME OF INFANTS (<5
kg) PRESENTING WITH ACUTE LIVER FAILURE
Girish Gupte, Ramalakshmi Ramiah, Lindsay Hogg, Evangeline Wassmer, Birmingham Children's Hospital NHS Trust, Birmingham, UK
Introduction: Acute liver failure in neonates is rare, but carries a high mortality. Neonatal liver failure can be defined as failure of the synthetic function of liver within 4 weeks of birth. Acute liver failure in neonates differs from children with regard to aetiology and outcome. Early diagnosis and referral to a pediatric liver centre is recommended as liver transplantation is the only definitive treatment when supportive or a disease-specific treatment fails. Very little is known about the developmental outcome in these children. We studied the long-term developmental outcome in neonates weighing less than 5 kg presenting to a national tertiary liver unit with acute liver failure.
Methods: Retrospective review of case notes was undertaken and PEDS (Parents’ Evaluation of Developmental Status) Parent questionnaire was sent out to parents of eligible patients. PEDS questionnaire elicits parents’ concerns regarding cognitive, language, self-help, personal-social, and motor skills.
Results: Eligible number of patients (<8yrs at the time of sending out questionnaires) were 25. Age on admission with acute liver failure ranged from 1 to 210 days. Aetiologies included GAL (galactosaemia), NNH (neonatal haemochromatosis), ALF due to HSV and undetermined causes. Questionnaire response received in 13 (52%). Gross and fine motor concerns were expressed in 23%. Expressive language concerns were present in 30%. Social/emotional and school concerns were present in 38%. Conclusion: Results from this study have provided quantitative information regarding developmental outcome in this cohort of patients.
157 TRANSIENT ELASTOGRAPHY MEASUREMENT OF LIVER AND SPLEEN STIFFNESS IN CHILDREN WITH BILIARY ATRESIA AS A NON-INVASIVE MARKER OF PORTAL HYPERTENSION
Harry Sutton, Tassos Grammatikopoulos, King's College Hospital, London, UK
Background: Children with biliary atresia (BA) have an increased risk of developing gastrointestinal (GI) varices secondary to portal hypertension (PHT). The diagnosis of PHT in children is often made by endoscopy, an invasive procedure to directly visualize any GI varices. Liver and spleen stiffness measurements have been suggested as non-invasive predictors of liver fibrosis.
Aim: Assess the feasibility and prognostic value of spleen stiffness measurements (SSM) and liver stiffness measurements (LSM) by transient elastography (TE; Fibroscan) in respect to PHT in children with BA.
Methods: A total of 76 patients (41 M) with BA underwent TE (64 had both LSM and SSM, 12 had only LSM) during a hospital visit. All patients had undergone a Kasai portoenterostomy and had their native liver and no ascites. Upper and lower surveillance GI endoscopies were performed in 34 patients, while 6 had emergency endoscopies due to acute GI bleeding.
Results: SSM by Fibroscan was feasible in 64 of 76 patients, while LSM was feasible in all 77. Median platelet count(PLT), haemoglobin(Hb), INR, albumin, bilirubin, aspartate aminotransferase(AST), alanine aminotransferase(ALT), alkaline phosphatase(ALP), gamma-glutamyl transpeptidase (GGT), spleen size, Clinical Prediction Rule (CPR) were 163x109/L, 116 g/L, 1.13, 40.1 g/L, 40.9 μmol/L, 124IU/L, 118IU/L, 584IU/L, 315IU/L, 13.5 cm and 216, respectively. LSM had a significantly higher success rate than SSM (88.4% vs. 72%, p = 0.02). SSM was not recorded in 12 out of 22 patients with normal spleen size. LSM and SSM were significantly higher in patients with any varices (31.6 and 47.7 vs. 16.6 and 14.6kPa, p = 0.003 and <0.001, respectively), with cut-off points of 21.1kPa and 22.5kPa giving AUC of 0.74 (p = 0.003) and 0.95 (p < 0.001) respectively; clinically significant varices (38.2 and 45.5 vs. 21.1 and 29.4kPa, p = 0.006 and 0.01, respectively), with cut-off points of 28.4kPa and 37.9kPa giving AUC of 0.76 (p = 0.001) and 0.73 (p = 0.006) respectively; active or a history of variceal haemorrhage (50.7 and 51.9 vs. 20.1 and 30.1kPa, p = 0.002 and 0.005) with a cut-off pointsof 31.8kPa and 25.7kPa giving AUC of 0.82 (p = 0.004) and 0.71 (p
= 0.04) respectively; and a CPR below the cut-off point of 116 (33.1 and 50.1 vs.. 18.8 and 22.8kPa, p = 0.002 and <0.001, respectively) with cut- off points of 23.3 kPa and 29.1kPa giving AUC of 0.72 (p = 0.001) and 0.86 (p < 0.001).
Conclusions: SSM and LSM by TE can be useful in the management of children with BA. Only 3 children, with GI bleeding, had SSM of 75 kPa suggesting a more reliable application in BA children. Both measurements have a predictive role in the diagnosis of PHT and presence of varices.
158 PERIPHERAL BLOOD MACROPHAGE ACTIVATION PATTERNS IN CHILDHOOD CHRONIC LIVER DISEASES
Hsiang-Hung Shih, Chih-Hsing Hung, Yu-Hsin Tseng, Min-Sheng Lee, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
Background: Macrophage polarization is an essential component of innate immunity and orchestras host pro-inflammatory (M1), pro-TH2 inflammation (M2a), immune regulatory (M2b), and tissue remodeling (M2c) signals upon incoming pathogens and toxic injuries. Differential patterns of M1/M2 macrophage activation have been implicated in the pathogenesis of hepatitis and liver fibrosis. The purpose of this study was to investigate the circulating macrophage populations and their specific M1/M2 polarization profiles in children with chronic liver diseases.
Methods: Thirteen patients, aged 1 to 15 years old, with chronic liver diseases (7 non-alcoholic steatohepatitis, 2 Wilson's disease, 2 biliary atresia, 1 choledochal cyst with post-operative cholangitis, 1 idiopathic chronic hepatitis) were enrolled in the study. Twenty-three school-aged children, admitted for growth hormone study, were assigned as the control group. Clinical symptoms, laboratory and image findings were recorded. Peripheral blood macrophage populations and polarization-related surface markers were evaluated by the flow-cytometry.
Results: Percentage of circulating macrophage-like populations (PM-2K+ CD14+) and macrophages (PM-2K+ CD14-) were higher in pediatric patients with chronic liver disease than the control (11.5% vs.. 5.1%, p = 0.09 and 4.5% vs. 0.1%, p < 0.01). Both the peripheral blood macrophage-like cells and macrophages showed suppressed M1 markers (CCR7+ CD86+, 17.4% vs. 64.3% and 6.9% vs. 29.6%; both p < 0.01). Contrarily, bias towards M2 polarization was found in the macrophage-like populations (M2a: CCR7- CXCR1+, 11.1% vs. 0.3%; M2b: CCR7- CD86+, 25.8% vs. 4.1%; M2c: CCR7- CCR2+, 15.2% vs. 2.5%; all p < 0.01) but not in the circulating matured macrophages (M2a 3.3% vs. 1.6%, p
= 0.23; M2b 6.4% vs. 6.4%, p
= 0.99; M2c 10.3% vs. 5.8%, p
= 0.21). Interestingly, nearly abolished M1 activation was observed in the circulating macrophages of patients with non-alcoholic steatohepatitis (0.1∼1.7%) and biliary atresia (0 and 0.5%).
Conclusions: Differential activation patterns of circulating macrophage populations were found in children with chronic liver diseases. Increased peripheral blood macrophages but low M1 expressions might imply depletion of pro-inflammatory innate immunity. However, lack of significant M2 polarization indicates a potential role of inadequate immune tolerance in the development of chronic liver disorder.
159 SPONTANEOUS PERFORATION OF BILE DUCT: A STUDY FROM A TERTIARY CARE HOSPITAL IN PAKISTAN
Huma Arshad Cheema, Hassan Suleman, the Children's Hospital & Institute of Child Health, Lahore, Pakistan
Spontaneous perforation of bile duct (SPBD) is a rare and often misdiagnosed entity. Despite being rare, it is still the second only to biliary atresia as the most common surgical cause of jaundice in infants. We describe 22 clinical presentations, treatments and outcomes in cases, which posed several diagnostic and management difficulties.
Patients & Methods: Over a 20-month period, 22 patients were seen with SPBD. Clinical presentation, biochemical abnormalities, imaging details and management as data wererecorded prospectively.
Results: Of these 22 patients, there were 12 males and 10 females age ranging in age from 1.5 months – 36 months. Presentation, biochemical parameters and imaging result are shown in the table. All 22(100%) had abdominal distension and ascites. 15 (68.2%) had jaundice at time of presentation, 6 (27.3%) had vomiting, 6 (27.3%) were febrile, 6 (27.3%) had abdominal pain, 5 (22.7%) had clear history of passing acholic stools, while 3 each (13.6%) had bilateral inguinal hernia and peritonitis. Choledochal cyst was seen in 7 (31.8%) andacquired biliary atresia in 1(4.5%). Elevated liver enzymes (ALT and AST) were present in 16 patients (72.7%) and 5 (22.7%) had bilirubin above 3 mg/dl. Coagulopathy was seen in 8 (36.6%) patients. Abdominal USG showed presence of ascites in all 22 (100%), hydrocele in 2 (9.0%), inguinal hernia in 1 (4.5%), choledochal cyst in 7(31.8%) and atretic gallbladder signifying acquired biliary atresia in one (4.5%) patient. HIDA scan was diagnostic in all 17 (77.27%) in which it was performed. MRCP was done in 3 (13.6%) patients. Most patients were managed with intravenous antibiotics, percutaneous drainage and t-tube insertion while patients with choledochal cysts required cholecystectomy with Roux-en-y choledochjejunostomy. Two patients(9.09%) died from surgical complications.
Conclusion: Spontaneous Perforation of Bile Duct should be suspected as an important cause of neonatal biliary ascites or peritonitis. Timely recognition and intervention is associated with favorable outcome.
160 NUTRITIONAL STATUS DYNAMICS ASSESSMENT IN CHILDREN WITH CHRONIC HEPATITS C DURING THE COMBINATION ANTIVIRAL THERAPY
Matinyan Irina, T. Strokova, T. Sentsova, A. Surkov, E. Pavlovskaya, M. Bagaeva, A. Zubovich, Federal Research Centre of Nutrition and Biotechnology, Moscow, Russian Federation
Background: Combination therapy (pegylated interferon + ribavirin) is the most effective treatment method of chronic hepatitis C in children now. It is known that one of the side effects of antiviral therapy is the reduction of appetite in infants which results in body weight decrease. The aim of the research is to assess the nutritional status of children receiving a course of combination antiviral therapy (pegylated interferon + ribavirin) in children with chronic hepatitis C.
Materials and Methods: Ninety-four children (46 girls and 48 boys in age from 3 to 17 years, mean age 10 years) with chronic hepatitis C received antiviral therapy (pegylated interferon 60 g / m2 - 1 time per week + ribavirin - 15 mg / kg / day daily). The assessment of nutritional status included measurement of body weight, height, calculation of body mass index (BMI) and BMI Z-score. Body composition was examined by impedance analysis, amounts of fat and lean body mass were measured. The assessment study was conducted before the start of therapy and after its termination.
Results: The therapy yields an average decrease in body weight by 3.9 kg (from 0.8 to 13 kg) in 80 children (85%). The median BMI z-score of the surveyed children before the start of antiviral treatment was 0.28 [-0,36- + 1.57] and after its termination -0.49 [-1,53–0,11], p
= 0.001. The initial value of fat body mass and lean body mass were 5.0 [3.3–10.2] and 14.3 kg [11, 6–23,1] kg, after completing the course of treatment of 5.4 [3,0–9,4] kg and 13, 8 [11,8–21,9] kg, p
= 0.28 and 0.01 respectively.
Conclusion: Combination antiviral therapy in children with chronic hepatitis C is accompanied by reduction of absolute amount of lean body mass and BMI Z-score reduction and thus requires timely administration of nutritional support.
161 DEATH IS RARE AND PROGRESSION TO TRANSPLANT IS SLOW, DESPITE A BURDEN OF PORTAL HYPERTENSION, IN LONGITUDINAL OUTCOMES OF ALPHA-1-ANTITRYPSIN DEFICIENCY FROM THE CHILDREN COHORT
Jeffrey Teckman1,18, Philip Rosenthal2,18, Lee Bass3,18, Karen F. Murray4,18, Nanda Kerkar5,18, John C. Magee6,18, Saul J. Karpen7,18, James E. Heubi8,18, Jean P. Molleston9,18, Robert Squires10,18, Binita M. Kamath11,18, Stephen Guthery12,18, Benjamin Shneider13,18, Kathleen M. Loomes14,18, Kieran Hawthorne15,18, Catherine A. Spino16,18, Ronald J. Sokol17,18,1Saint Louis University, Cardinal Glennon Children's Medical Center, St. Louis, MO, USA,2University of California, San Francisco, San Francisco, CA, USA,3Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA,4University of Washington Medical Center, Seattle Children's, Seattle, WA, USA,5Childrens’ Hospital of Los Angeles and Mount Sinai, Los Angeles, CA, USA,6University of Michigan Medical School, Ann Arbor, MI, USA,7Emory University School of Medicine/Children's Healthcare of Atlanta, Atlanta, GA, USA,8Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA,,9Indiana University School of Medicine /Riley Hospital for Children, Indianapolis, IN,USA,10Children's Hospital of Pittsburgh, Pittsburgh, PA, USA,11Hospital for Sick Children and University of Toronto, Toronto, ON, Canada,12University of Utah, Salt Lake City, UT, USA,13Baylor College of Medicine, Houston, TX, USA,14Children's Hospital of Philadelphia, Philadelphia, PA, USA,15Arbor Research Collaborative for Health, Ann Arbor, MI, USA,16University of Michigan, Ann Arbor, MI, USA,17University of Colorado, Aurora, CO, USA,18ChiLDReN Network
Background: The Childhood Liver Disease Research Network (ChiLDReN) is a longitudinal study of pediatric liver diseases, including subjects with alpha-1-antitrypsin deficiency (AAT), aiming to document the natural history in North America, identify predictors of clinical outcomes and identify disease modifiers.
Objective: Summarize and identify predictors of clinical outcomes, including portal hypertension (PHT), liver transplantation and death, in AAT subjects with native liver.
Methods: PIZZ and PISZ subjects, 0–25y, have enrolled since November 2007 at 14 North American tertiary care centers, with liver disease as defined by having one of: neonatal cholestasis, chronically elevated AST, ALT or GGT (>1.25xULN), chronic hepatomegaly, clinical findings or complications of PHT or cirrhosis, impaired liver synthetic function, or liver biopsy abnormalities other than globular inclusions. Baseline visits recorded data from medical records, history, physical exam, laboratory, imaging and other information obtained as part of routine clinical care, that were updated at prospective annual visits. PHT was defined as: (1) history of a complication of PHT (variceal hemorrhage, ascites, or hepatopulmonary syndrome) or (2) clinical findings consistent with PHT (splenomegaly [spleen > 2 cm below the costal margin] or thrombocytopenia [platelet count < 150,000]). PHT was “absent” if none of the criteria were met. Available clinical studies (ultrasounds, endoscopies, etc.) were examined to confirm the PHT assignment. Kaplan-Meier methods and Cox regression were used to analyze time to event and correlated longitudinal dichotomous outcomes. 71 subjects with liver transplant prior to enrollment are not included in this analysis.
Results: 301 subjects enrolled with native liver (60% male). 223 (74%) entered the cohort without PHT, and approximately 3% of these developed PHT per year (Table 1). 27 of 301 had liver transplants during 790 person-years of follow-up. 25 of the 27 subjects transplanted entered the cohort with PHT. One death was reported following transplant. Physical exam and laboratory measures associated with future development of PHT included changes in weight, height, head circumference, INR, total bilirubin, AST, and GGTP (p < 0.05), although small numbers of events has so far prohibited the development of a predictive algorithm with useful specificity. Significantly lower height Z-scores, mid arm circumference, and triceps skinfold thickness were seen after development of PHT compared to those without PHT (p < 0.05).
Conclusions: Children and young adult AAT patients at tertiary care centers have a significant burden of PHT, affecting growth parameters, but progress slowly to liver transplant. Death is very rare in the transplant era. PHT almost always precedes transplant by several years. The specificity of predicting clinical outcomes will require more study. There is likely an important role for unidentified genetic and environmental modifiers.
162 THE ROLE OF TRANSIENT ELASTOGRAPHY IN THE ASSESSMENT OF CYSTIC FIBROSIS-ASSOCIATED LIVER DISEASE
Jessica Woolfson1, Shravaan Raveendran2, Mark Chilvers1, Rick Schreiber1, Orlee Guttman1,1British Columbia Children's Hospital, Vancouver, BC, Canada,2University of British Columbia, Vancouver, BC, Canada
Background: Cystic Fibrosis-associated liver disease (CFLD) occurs in 30% of patients, and 10% develop advanced fibrosis. CFLD manifests by age 18 in 90% of cases and is the third most common cause of mortality in CF patients. CFLD diagnosis and monitoring are challenging as specific tests for detection have not been developed and existing investigations do not correlate well with presence or severity of disease. The Aspartate Aminotransferase Platelet Ratio Index (APRI) is one tool that has been validated as a surrogate marker of hepatic fibrosis in other chronic liver disease.
Transient Elastography (TE) is a novel, rapid, non-invasive method for assessing liver stiffness (LS). Studies suggest it may be valuable in the assessment of liver fibrosis in pediatric patients with liver disease, though its role in detecting CFLD has only begun to be explored. The purpose of this study was to assess the utility of APRI and TE in identifying liver fibrosis in pediatric CF patients.
Methods: Patients 2–18 years were recruited from the British Columbia Children's Hospital Cystic Fibrosis clinic. Patients were determined to have CFLD using standard criteria. Where the original basis for CFLD diagnosis was unclear from chart review, patients maintained on ursodeoxycholic acid were included in the CFLD group. Charts were reviewed for demographic and clinical data. Each patient underwent TE by a trained operator.
Results: Of the 55 patients that were included in the study (50.9% male, mean age 11.6 (3.8) years) 49% were homozygous for ΔF508 gene and 22 patients had CFLD. All mean liver enzymes were higher in the CFLD group, significantly ALT (p
= 0.031) and ALP (p = 0.030). Mean LS as determined by TE was higher in the CFLD group (5.92 vs. 4.54; P 0.0147). APRI was higher in the CFLD group but not significantly different (0.396 vs. 0.324, p
= 0.119). Linear regression showed a mild positive association between TE and APRI (Slope 0.058 +/- 0.01,CI 0.038–0.79, R2 0.386).
Discussion: CFLD is one of the leading causes of morbidity in CF, but limitations of existing tests hamper diagnosis and monitoring. Liver stiffness scores were higher in CFLD patients and correlate with APRI values, suggesting that TE may have clinical applications for identifying and following patients with this condition. Further studies are needed to determine the role of TE in CFLD.
163 LIVER SIZE AND GALLBLADDER ABNORMALITIES IN PATIENTS WITH EXTRAHEPATIC PORTAL VEIN OBSTRUCTION
Natascha Silva Sandy, Juliana Corrêa Campos Barreto, Gabriela de Souza Gomez, Flávia Andressa Justo, Maria Ângela Bellomo Brandão, Roberta Vacari de Alcântara, Adriana Maria Alves de Tommaso, Roberto Massao Yamada, Gabriel Hessel, Faculty of Medical Sciences - University of Campinas, São Paulo, Brazil
Background: The extrahepatic portal vein obstruction (EHPVO) is a vascular disorder characterized by an obstruction of the extrahepatic portal vein, with or without involvement of the intrahepatic portal vein or splenic vein or superior mesenteric vein. In many studies, EHPVO is reported as a major cause of portal hypertension in pediatric patients. An abdominal ultrasonography allows evaluation of liver size and gallbladder abnormalities. Modifications in blood flow resulting from EHPVO have been associated with the decreased liver size, and this phenomenon could be related with an increased incidence of gallbladder varices and gallstones.
Objectives: The aim of the present study was to assess the changes in liver size and gallbladder ultrasonographic findings in patients with extrahepatic portal vein obstruction, and study the correlation between the presence of gallstones and reduced liver size.
Methods: The study included 82 patients with EHPVO followed at university hospital. Ultrasonography was done using a Toshiba Power Vision 6000 with sectorial (3,75 MHz) and linear (5 MHz) transducers. References of normal liver size were based on tables established by Konus et al. The presence of gallstones, biliary sludge and gallbladder wall thickening (greater than 2.5 mm) were investigated. Statistical analysis was performed using Chi-square and a 5% significance level was adopted.
Results: The average age at the moment of ultrasonografic evaluation was 14.5 years, with a median of 13.4 years; 65% (n = 53) of subjects were male and 35% (n = 29) female. Reduction in liver size was observed in 41.5% (n = 34). The prevalence of gallbladder ultrasonographic findings was 73% (n = 60) – gallbladder wall thickening/gallbladder varices being the most common finding (58.5% - n = 48), followed by gallstone (14.5% - n = 12), however 8 patients had both. In 4 cases, gallbladder was not assessed through ultrasonography due to previous cholecystectomy. No examination showed the presence of biliary sludge. In the group of patients with gallstones (n = 12), 50% (n = 6) presented reduced liver size and the same number had a normal liver size – no statistically significant difference was observed (p > 0.05). In the other hand, occurrence of gallbladder wall thickening / gallbladder varices were observed in 27 out of 34 patients with reduced liver size, establishing a statistically significant association (p < 0.05).
Conclusions: In the present study, we observed a reduced liver size in almost half of patients with EHPVO, as well as a higher frequency of biliary lithiasis when compared with the general pediatric population. An association between reduced liver size and gallbladder wall thickening/gallbladder varices, but not with cholelithiasis, was observed. It is likely that the pathogenesis of gallstones is not related to decreased blood flow, which should be the main factor involved in liver reduction.
164 LONG-TERM BENEFIT OF SEBELIPASE ALFA OVER 52 WEEKS IN CHILDREN AND ADULTS WITH LYSOSOMAL ACID LIPASE DEFICIENCY (ARISE TRIAL)
Katryn Furuya1, Sachin Marulkar2, Mark Friedman2, Radhika Tripuraneni2, Barbara K. Burton3,1Alfred I. duPont Hospital for Children, Wilmington, DE, USA,2Alexion Pharmaceuticals, Inc., New Haven, CT, USA,3Northwestern University Feinberg School of Medicine, Ann and Robert H. Lurie Children's Hospital, Chicago, IL, USA
Background: Lysosomal acid lipase deficiency (LAL-D) is a progressive multisystem disease that is an underappreciated cause of cirrhosis, severe dyslipidemia, and early-onset atherosclerosis.
Methods: Affected children and adults (n = 66; median age 13 y, range 4–58 y) were randomized to placebo (PBO) or sebelipase alfa (SA) 1 mg/kg every other wk (qow) for 20 wk in the phase 3 trial (ARISE; NCT01757184). After 20 wks, ALT normalization (the primary endpoint) was achieved in 31% of the SA group and 7% of the PBO group (p
= 0.0271). Multiple secondary efficacy endpoints were also met. After the double-blind period, 65 participants entered an ongoing open-label extension in which they all received SA. We report efficacy at 52 weeks of SA exposure for all subjects, representing 1693 infusions of 1 mg/kg qowand 13 infusions of 3 mg/kg qow. Safety analysis results from the open-label period involves subjects with between 86 and 152 weeks of SA exposure (week 22 to January 26, 2016).
Results: After 52 weeks of SA exposure, 47% (29/62) achieved ALT normalization and 56% (33/59) achieved AST normalization, with 73% of subjects reaching ALT ≤1.5 x ULN and 85% of subjects reaching AST ≤1.5 x ULN. Upon crossing over to SA, the PBO group exhibited marked and sustained improvements in ALT and AST mirroring those seen in the SA group during the double-blind phase, whereas those in the SA/SA group sustained the improvements they had achieved in the first 20 weeks. Mean baseline values for LDL-C (199.2 mg/dL), non-HDL-C (230.0 mg/dL), and triglycerides (153.9 mg/dL) decreased by -30%, -29%, and -23%, respectively, after 52 wk of SA exposure; mean HDL-C (baseline 32.5 mg/dL) increased by 24%. Liver fat and volume were reduced by 25% and 13%, respectively. Most adverse events (AEs) in the open-label period were mild to moderate in severity. Similar to the profile seen during the double-blind portion, patients most commonly experienced headache, nasopharyngitis, cough, and pyrexia. Four subjects had serious AEs of which 1 was treatment-related (an infusion-associated reaction). Twelve subjects (19%) experienced infusion-associated reactions, which were mild or moderate in severity in all but 1 subject. There were no discontinuations due to an AE. Six (9%) of the 66 subjects had at least 1 positive anti-drug antibody (ADA) sample; of these, 2 developed neutralizing antibodies. The safety profile for ADA-positive subjects was consistent with that of the overall study population.
Conclusion: SA was well tolerated and the long-term safety profile was similar to the profile seen during the double-blind portion. Long-term treatment with SA produced early and rapid improvements in markers of liver injury and lipid abnormalities which were sustained: reductions in serum aminotransferases, increasing proportion of patients achieving ALT/AST normalization, sustained improvement in lipid levels, and reduction of liver fat and volume through 52 weeks of SA treatment.
165 A COMPARISON OF THE EFFECTS OF THYMOQUINONE, SILYMARIN AND N-ACETYLCYSTEINE ON LIVER INJURY INDUCED BY CARBON TETRACHLORIDE
Kaan Demiroren1, Mehmet Turan Basunlu, Remzi Erten2, Erdem Cokluk2,1University of Medical Sciences, Yuksek Ihtisas Teaching Hospital, Bursa, Turkey,2Yuzuncu Yil University, Dursun Odabas Medical Center, Van, Turkey
Objective: Although liver diseases, some of them having high morbidity and mortality rates, are common, treatment methods and drugs used to stop the process are limited. Different studies reported that thymoquinone, silymarin, and N-acetylcysteine had a positive effect on hepatic pathologies. In this study, thymoquinone, silymarin, and N-acetylcysteine were administered to the rats with hepatic injury induced by carbon tetrachloride (CCl4) and the effects of these agents were investigated.
Methods: A total of 50 male Wistar albino rats, 8–12 weeks old, were randomly allocated into 5 groups, consisting of 10 rats each, as follows: Group I (CCl4), group II (thymoquinone and CCl4), group III (silymarin and CCl4), group IV (N-acetylcysteine and CCl4), group V (control group). CCl4 (1.5 mL/kg, as a mixture of CCl4: olive oil, 1:2, intraperitoneally) was administered twice-weekly, thymoquinone (10 mg/kg, intraperitoneally), silymarin (100 mg/kg, every day, intraperitoneally), and N-acetylcysteine (10 mg/kg, every day, intraperitoneally) daily during four weeks. Blood and liver analyses were performed. The results were evaluated as statistically via Kruskal Wallis and Duncan's tests. P value <0.05 was considered statistically significant.
Results: The mean weight of rats included in the study was 225.6 g (range: 167- 350 g). During the study, nine rats died (four in group II, one in group IV, two in group III, and two in group I). Two rats in control group were excluded from the study. Thymoquinone, silymarin, and N-acetylcysteine improved the levels of alanine aminotransferase, tumor necrosis factor-α, transforming growth factor–β platelet-derived growth factor- BB, and interleukin-6 which were increased by CCl4 (p < 0.05). N-acetylcysteine and silymarin significantly increased liver reduced glutathione levels which were decreased by CCl4 (p < 0.05). Thymoquinone, silymarin, and N-acetylcysteine improved blood total oxidant status (p < 0.05). In the histopathological and immunohistochemical examination of liver tissue, three agents decreased necrotic cell count and inflammatory cell count, and mitosis (p < 0.05), but not fibrosis score (p > 0.05). Statistically significant decreasing in α-SMA stained hepatic stellate cell count was seen with only thymoquinone (p < 0.05). Blood and liver test results are seen in Table as a median values.
Conclusions: Thymoquinone, silymarin, and N-acetylcysteine have the potential importance for the treatment in diseases causing liver injury.
∗166 SPLICING ANALYSIS USING INDUCED PLURIPOTENT STEM CELL-DERIVED HEPATOCYTE-LIKE CELLS GENERATED FROM A PATIENT WITH PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTATSIS TYPE 2
Kazuo Imagawa1, Ryo Sumazaki1, Shigemi Isoyama1, Ken Tanikawa2, Masato Shinkai3, Masayoshi Kage2,1University of Tsukuba, Tsukuba, Ibaraki, Japan,2Kurume University Hospital, Kurume, Fukuoka, Japan,3Kanagawa Children's Medical Center, Yokohama, Kanagawa, Japan
Background: The bile salt export pump (BSEP) is a key molecule that transports bile acid into the biliary canaliculi in humans. Progressive familial intrahepatic cholestasis type 2 (PFIC2) is mainly characterized by BSEP deficiency, which is followed by intrahepatic cholestasis. Because the expression of BSEP gene is only observed in hepatocytes among human somatic cells, the spliced form of BSEP mRNA cannot be analyzed using other types of cells. It is difficult to obtain biopsy samples of the liver, although blood cells and dermal fibroblasts are often used to analyze genomic DNA. Recently, patient-specific induced pluripotent stem cells (iPSCs) and their derivatives are expected to become a novel disease model. Therefore, to analyze the spliced form of BSEP mRNA, we attempted to obtain hepatocytes derived from PFIC2 patient-specific iPSCs.
Methods: One healthy donor and a PFIC2 patient participated in the present study. A patient was diagnosed with PFIC2 based on the presence of compound heterozygous mutations in BSEP gene (c.-24C>A and c.2417G>A) and liver histology results. The iPSCs were generated from blood cells obtained from the participants (Control-iPSCs and PFIC2-iPSCs) by using a Sendai virus vector expressing Yamanaka factors. The iPSCs were then differentiated into hepatocyte-like cells (HLCs). Total RNA was extracted from the iPSCs and HLCs. The sequence of BSEP mRNA was analyzed using the cDNA synthesized from total RNA.
Results: We successfully obtained iPSCs from blood cells. These iPSCs were positive for OCT4 and expressed markers specific to human embryonal stem cells. The HLCs were obtained on day 25 after hepatocyte differentiation. Immunostaining analysis for HLCs indicated bile canaliculi between the cells were observed by electron microscopy. The HLCs were positive for albumin and abundantly secrete albumin into the culture medium. To examine whether the BSEP mutation in the 5 f-UTR (c.-24C>A) would cause aberrant splicing in the HLCs derived from PFIC2-iPSCs (PFIC2-HLCs), direct sequence analysis of BSEP cDNA was performed. The exon 2 sequence of BSEP cDNA was heterozygously eliminated in the PFIC2-HLCs.
Conclusion: We could analyze the spliced form of BSEP mRNA using PFIC2 patient-specific iPSC derived hepatocyte-like cells.
167 HISTAMINE CORRELATES WITH LIVER FIBROSIS IN BILIARY ATRESIA
Kejun Zhou, Wei Cai, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, China
Background and Aims: Biliary atresia is a severe neonatal cholestasis disease that is caused by obstruction of extra bile ducts. Liver fibrosis progresses dramatically in biliary atresia, and the underlying molecular mechanism is largely unknown.
Methods: Amino acids and biogenic amines were quantified by targeted metabolomic methods in livers of 52 infants with biliary atresia and 16 infants with neonatal hepatitis syndrome. Normal adjacent nontumor liver tissues from 5 hepatoblastoma infants were used as controls. Orthogonal partial least-squares discriminant analysis was used to identify the differences between biliary atresia, neonatal hepatitis syndrome, and control tissues. Histamine metabolism enzymes and receptors were analyzed by immunohistochemistry and Western blot.
Results: The orthogonal partial least-squares discriminant analysis clearly separated biliary atresia from neonatal hepatitis syndrome and the controls using amino acid and biogenic amine profiles. Histamine was significantly increased in the livers of biliary atresia infants and was positively correlated with the severity of fibrosis. This finding was supported by the elevated L-histidine decarboxylase and reduced monoamine oxidase type B expressions in the biliary atresia infants with severe fibrosis. Furthermore, histamine receptor H1 was observed in the cholangiocytes of biliary atresia livers.
Conclusions: Histamine was positively correlated with fibrosis and may be a potential target to prevent liver fibrosis in biliary atresia.
168 STERILE CEREBROSPRINAL FLUID ASCITES: A RARE COMPLICATION AFTER VENTRICULOPERITONEAL SHUNTING
Kristen Critelli, James Squires, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
Sterile cerebrospinal fluid ascites is a rare complication following ventriculoperitoneal shunt placement and should be considered in shunted patients who present with ascites. While the exact etiology is unknown, suggested mechanisms include insufficient absorption due to pathology within the peritoneum, possibly related to the silicone tubing. Treatment for sterile ventriculoperitoneal shunt-associated ascites involves diversion of the draining cerebrospinal fluid, typically by converting to a ventriculoatrial shunt. We describe a patient with a ventriculoperitoneal shunt found to have sterile ascites which responded to cerebrospinal fluid re-direction.
A 20-year-old male with cerebral palsy, seizure disorder, Dandy Walker syndrome, and hydrocephalus status post ventriculoperitoneal shunt placement at birth with revision at 14 years of life secondary to shunt malfunction presented with a four-month history of progressive abdominal distension. He had no history of shunt infection or abdominal surgery. Results of routine blood tests were notable for anemia with a hemoglobin of 10.5 mg/dL, hypoalbuminemia with an albumin of 2.0 g/dL, and an elevated erythrocyte sedimentation rate of 39 mm/h. A pre-albumin was also found to be low, and his hypoalbuminemia was attributed to poor nutritional intake. Additional markers of synthetic hepatic function were normal. An abdominal ultrasound showed a large amount of ascitic fluid with a coarse echotexture of the liver but patent hepatic vessels with normal directional flow. Abdominal computed tomography showed extensive ascites but normal appearing liver. Paracentesis revealed clear fluid, 41 leukocytes per cubic millimeter (86 percent lymphocytes) and a protein level of 2.7 g/dL; cytologic examination showed no malignant cells. The serum-ascites albumin gradient was less than 1.1 g/dL. No organisms grew in cultures of ascitic fluid, and the CSF-specific transferrin beta-2 was negative. Laparoscopy revealed a grossly erythematous peritoneum and a normal appearing liver. Liver biopsy showed minimal ductular reactivity with no evidence of hepatitis or fibrosis, and a peritoneal biopsy revealed fibrosis and chronic inflammation. The ventriculoperitoneal shunt was externalized and later internalized to a ventriculoatrial shunt with resolution of abdominal distension. Repeat abdominal ultrasound six weeks later showed improved ascites without evidence of re-accumulation.
While silicone and its constituents do not cause specific immune responses, silicone shunts can degrade over time and elicit a nonspecific inflammatory reaction. It is quite possible that an inflammatory reaction to the silicone tubing used in the creation of our patient's ventriculoperitoneal shut was a cause of his sterile ascites. Additionally, the sensitivity of transferrin beta-2 to detect CSF in ascitic fluid may be lower than its reported ability in other fluids.
169 AGE, FIBROSIS AND SUCCESS OF KASAI HEPATOPORTOENTEROSTOMY IN BILIARY ATRESIA: IS THERE A CORRELATION?
Krupa Mysore, Sanjiv Harpavat, Kalyani Patel, M. John Hicks, Texas Children's Hospital, Houston, TX, USA
Background: Biliary atresia (BA) is a progressive cholestatic liver disease associated with development of biliary cirrhosis. It is unclear why infants with biliary atresia who undergo Kasai Hepatoportoenterostomy (KHPE) later (after 90–120 days) are less likely to benefit. One possible hypothesis is that older infants have advanced fibrosis which impairs the success of KHPE. To test this, we analyzed infants with BA who underwent percutaneous liver biopsy as part of their diagnostic evaluation at Texas Children's hospital. We examined the correlation of degree of fibrosis at needle liver with age of the infant, secondly the degree of fibrosis with success of KHPE.
Methods: Charts of infants with subsequent diagnosis of BA born between 2011 and 2014 were reviewed. Patients who underwent needle liver biopsy as part of their diagostic evaluation were included. Infants with BA who had liver biopsy at a referral hospital or a wedge biopsy at our institution were excluded. Demographic data for all patients and age at which conjugated bilirubin normalized in patients who received KHPE were obtained. We defined successful KHPE as conjugated bilirubin of < 0.2 mg/dL at 3 months post KHPE. For each patient trichrome stained slides were de-identified and two pathologists blindly scored the degree of fibrosis. Stage of fibrosis was defined by Batts and Ludwig four tier system in patients with an adequate sample (≥7 portal tracts). The Pearson correlation coefficient was calculated using STATA13, and Student's t-test was used to compare mean fibrosis.
Results: Twenty-five infants subsequently diagnosed with BA underwent needle liver biopsy at a median age of72 days (15–158 d). One subject was excluded due to inadequate tissue sample. 18/24 infants were female (75%) and 2(8%) had syndromic features. 14/24 (58%) had KHPE following needle biopsy (median age at KHPE 59.5 days (22d-96d) and at liver needle biopsy 53.5 days (15–93 d). The average fibrosis in the KHPE group was 3.25 (range 2–4). 7/14 (50%) had successful KPE with average fibrosis score of 3.5 (2.5–4). The degree of fibrosis was similar in infants with successful and unsuccessful KHPE (p 0.15) 10/24 (42%) did not undergo KHPE, median age 117.5 days (71–158 d) with average fibrosis score of 3.5 (range 2–4). The inter-rater agreement, kappa statistic for pathologists was 0.25 (p = 0.008). There was no correlation between age and degree of fibrosis with correlation coefficient, r 0.12 (CI -0.28 to +0.49, p = 0.5).
Discussion: First our study demonstrates that extensive liver fibrosis is found in all ages in BA and fibrosis is not correlated with age of infant in BA. Second, the success of the KHPE is not related to degree of fibrosis. Infants with successful and unsuccessful KHPE had similar average fibrosis scores on percutaneous liver biopsy. Our findings suggest that patients should not be denied KHPE based on fibrosis when predicting whether or not an infant would benefit from KHPE.
170 UGT1A1 GENOTYPES AND UNCONJUGATED HYPERBILIRUBINEMIA PHENOTYPES IN POST-NEONATAL CHINESE CHILDREN: A QUANTITATIVE CORRELATION AND FUNCTIONAL ANALYSIS
Kuerbanjiang Abuduxikuer, Jian-She Wang, Children's Hospital of Fudan University, Shanghai, Shanghai, China
Background: Uridine-diphosphoglucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) is the key enzyme that catalyzes the glucuronidation of bilirubin. Previous reports on UGT1A1 sequencing among Mainland Chinese children with hyperbilirubinemia focused on either newborns, or small number of cases. Full spectrum of quantitative genotype-phenotype correlation data on post-noenatal children were lacking. Earlier functional research mainly focused on A(TA)7TAA variant which is more prevalent among Caucasians, and little attention has been given to G71R, and Y486D that commonly occurs in yellow-skinned East Asians.
Objectives: To quantitatively correlate UGT1A1 genotypes to all post-neonatal phenotypes of unconjugated hyperbilirubinemia (UCH) among Chinese children, and to functionally analyze the effect of G71R+Y486D combined variant.
Methods: Aims of this study were to quantitatively analyze the UGT1A1 genotype-phenotype correlation among Chinese children with unconjugated hyperbilirubinemia, to elucidate the clinical significance of complex UGT1A1 genotypes that occurred in a single patient (multiple SNPs, SNP plus mutation, and multiple mutations), and to expand UGT1A1 variant spectrum by discovering novel mutations or variants. We retrospectively reviewed UCH patients, used Chi-square and single/multiple logistic regression analyses for the quantitative genotype-phenotype correlation. Recombinant wild-type, G71R, Y486D, and G71R+Y486D variants of UGT1A1 proteins were used to determine enzyme activity towards various substrates.
Results: 74 cases including 21 PUCH (Prolonged Unconjugated Hyperbilirubinemia), 30 GS (Gilbert Syndrome), 22 CNS-II (Crigler Najjar Syndrome type II), and 1 CNS-I phenotypes were analyzed. Total of 21 variants, including 7 novel variants were found. In the multiple regression model that all other variants were controlled, heterozygous A(TA)7TAA, G71R/P364L, and Y486D/other mutations were significantly associated with increased risk of GS, PUCH, and CNS-II, respectively. Total allele number is significantly associated with GS and CNS-II, with each increase in total allele number, the odds ratio (OR) of having GS and CNS-II increased by 1.46 and 4.47 fold, respectively. UGT1A1 gene variants reduced the enzyme activity, the enzyme activity of G71R variant is 57% that of the wild-type. Y486D, and G71R+Y486D variant have the lowest enzyme activity with 29%, and 28% that of wild-type. Affinities of G71R, Y486D, and G71R+Y486D towards bilirubin and acetaminophen were lower than the wild-type.
Conclusion: We detected 7 novel variants, and quantitatively calculated risks of having specific phenotypes using genetic data. G71R, Y486D, and G71R+Y486D variants affected recombinant UGT1A1 enzyme activities towards various substrates.
171 EFFECT OF AGE IN THE PRESENTATION AND OUTCOME OF CHOLEDOCHAL CYST AMONG FILIPINO INFANTS AND CHILDREN
Novette Regina M. Lagunzad, Germana V. Gregorio, University of the Philippines - Philippine General Hospital, Manila, Metro Manila, Philippines
Background: Choledochal cyst is a rare hepatobilary congenital anomaly with age-associated clinical manifestations. While this has been reported in other countries, the different features and outcome of choledochal cyst in infants as compared to older children had not been investigated locally. Knowledge of these differences is important for early recognition and prompt treatment of the disease to prevent adverse outcomes.
Objective: To compare the clinical, biochemical, anatomical and histological features and outcome of infants and children diagnosed with childhood choledochal cyst.
Study Design: Retrospective cohort.
Methods: From 2004–13, the medical records of 100 choledochal cyst patients from a tertiary hospital were reviewed and classified into the infant group (n 32, 53% girls) or classic pediatric group (n = 68, 74% girls) based on the age at presentation.
Results: Jaundice, acholic stools and clinical (all p < 0.001) and histological (p 0.467) evidence of cirrhosis were more common in the infant group; while abdominal pain and vomiting (both p < 0.001) were predominant in the classic pediatric group. Median total bilirubin (10.9 mg/dl vs. 2.8), AST (156 IU/L vs. 82), ALT (101 IU/L vs. 72) were significantly higher, albumin (26 g/L vs. 32) lower and prothrombin time (1.35 sec. off vs. 0) more deranged in the infant group. Todani type 1a was the commonest choledochal cyst type in both groups. Preoperative morbidities of sepsis and upper gastrointestinal bleeding (both p = 0.001) were more frequent in the infant group while choledocholithiasis (p 0.033) was prevalent in the classic pediatric group. Seventy-two patients underwent choledochal cyst excision (47% of infant; 84% of classic pediatric group) while 9 had drainage procedure only. No surgery was done on 9 with Caroli's disease, 7 with cirrhosis and 3 with septicemia. Over a median follow-up of 5 months, 59% of the classic pediatric groups are alive without liver disease while 66% of the infant group died or required liver transplant.
Conclusion: Infants diagnosed with choledochal cyst have a more severe clinical, biochemical and histological features with poorer outcomes as compared to the older group.
172 IMPACT OF THE TIMELY DETECTION PROGRAM IN ITS TERTIARY CARE-LEVEL PHASE OF BILIARY ATRESIA BY MEANS OF THE VISUAL COLORIMETRIC STOOL CARD
V.G. López-Flores, M.C. Bojórquez-Ramos, J.C. Barrera de León, S. Jimenez-Sánchez, R. Macías-Rosales, Y.A. Castillo de León, UMAE Hospital de Pediatría CMNO IMSS, Guadalajara, Jalisco, México
Introduction. Biliary atresia (BA) is responsible for 50% of indications for liver transplantation in pediatric population and should always be considered as probable diagnosis at any infant who remains jaundiced at 2 weeks of age and needs to be evaluated for cholestasis. Timely detection can be carried out by the Visual Colorimetric Stool Card (VCSC), in that it allows to identify different grades of hypoacholia or acholia, for which it has been described as convenient, simple, and cost-effective.
Objectives: To determine the impact of the BA timely detection program through the VCSC in its tertiary care-level phase.
Materials and Methods: Descriptive study, comprising the period from January 2013 to December 2015, including patients admitted with a diagnosis of cholestatic syndrome. Demographic, clinical, and medical consultation characteristics were registered, as well as age at surgical bile-duct exploration, the Kasai-type surgical procedure, and its reference by the timely detection program through VCSC.
Results: Seventy six patients were included, with a median age at admission of 72 days (range, 28–30 days), feminine gender 38.1%. BA was diagnosed in 19 patients (25%), feminine gender predominated (52.6%), with a median age at admission of 120 days. In six cases (31.5%), the mothers of the patients had knowledge of the VCSC. Only four patients were admitted (5.26%) through the timely detection program by VCSC, two of these with BA, who were submitted to Kasai-type surgical derivation at an age of < 60 days.
Conclusions. No positive impact has been reported in terms of diagnostic and therapeutic opportunity after implementation of the BA timely detection program through the VCSA. There should be greater emphasis placed on the BA timely detection program.
173 EPIDEMIOLOGICAL DATA FROM ASYMPTOMATIC PATIENTS WITH PERSISTENT HYPERTRANSAMINASEMIA
Maria Rogalidou, Theodoros Palianopoulos, Evangelia Kritikou, Antigone Siamopoulou-Mavridou, Nikolaos Chaliasos, University Hospital of Ioannina, Ioannina, Greece
Introduction: The measurement of serum transaminase levels has become part of the routine biochemical evaluation in many countries. An investigation of unexpected hypertransaminasemia is important for differentiating muscular and hepatic disease; to institute timely and specific treatment for progressive, but still asymptomatic, treatable liver conditions.
Purpose of the present study was to analyze the epidemiological data of asymptomatic patients with persistent hypertransaminasaimia.
Material and Methods: The study population consisted 42 patients (12 females and 30 males) mean age 5.3 years (2 months - 15.5 years) who were examined in pediatric gastroenterology outpatient clinic during the last 5 years because of persistent asymptomatic hypertransaminasaimia. The medical files of all patients were reviewed and data (body weight, height, age, sex, duration of hypertransaminasaimia, & investigations made) were recorded. The investigations made were: full blood count, CRP, thyroid hormones and extended hormonal investigations when considered, bilirubine, gGT, LFT, BUN, Creatinine, CPK, Aldolase, Fe, Ferritin, antibodies for hepatotropic infection agents, celiac antibodies, Immunoglobulins, antibodies for autoimmune hepatitis, blood gazes, a1AT, Ceruloplasmine, Cu (blood/urine), a-FP, aminograms, lipid profile, sweet test and liver ultrasound.
Results: Definite diagnosis was made in 15/42 (35.7%) of patients. Three patients, (7%) had celiac disease without other manifestations and the hypertransaminasaimia recovered 2–7 months after gluten free diet. In one girl, a 1AT deficiency was detected. Muscular dystrophy was diagnosed in four children (boys) 9.5%). One boy had persistent CMV infection without other manifestations and two boys had chronic active HBV infection. One girl, infant, was diagnosed with biliary atresia. Glycogen storage disease type IXwas diagnosed in one toddler (boy). Autoimmune hepatitis type I was found in one adolescent (girl) and Wilson's disease in one adolescent boy and they are under treatment. Non-alcoholic fatty liver disease was suspected in one adolescent boy. In 8 patients elevation only of AST was observed and Macro-AST condition was suspected but has not been identified yet. One girl with Down syndrome had elevated auto antibodies for autoimmune hepatitis but biopsy was normal and has not fulfill the criteria for that diagnosis. In one patient elevation of muscular enzymes has been observed but genetic test were negative and definite diagnosis no made yet. In 7 patients hypertransaminasaimia resolved spontaneously during the follow-up without to have diagnosis. Two patients continues to have transaminasamia without diagnosis and 7 patients were lost from the follow-up.
Conclusions: Persistent asymptomatic transaminasaimia in children should be stepwise investigated. Several treatable conditions could be the etiological factor for its appearance.
174 INFECTIONS CAUSE SIGNIFICANT MORBIDITY IN CHILDREN WITH ACUTE VARICEAL BLEEDING
Marta Carneiro de Moura, Shiyi Chen, Binita M Kamath, Vicky L Ng, Simon C Ling, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
Background and Aim: The morbidity and mortality associated with acute variceal bleeding (AVB) in children have been poorly characterized. Because death from the first bleed seems to be unusual, the need for primary prophylaxis in children is unclear and depends largely on the extent of the associated morbidity, including infection. We aimed to measure the morbidity associated with AVB in children caused by infections.
Methods: Retrospective study of AVB episodes between May 2000 andMay 2015. We included children with liver disease or portal vein thrombosis who presented with acute upper gastrointestinal bleeding requiring volume support and/or red cell transfusion if endoscopy confirmed the presence of varices.
Results: We identified 70 episodes of AVB in 57 children (median age 6 y, 52% female). 47 (67%) episodes were the patient's first AVB. 33 (58%) patients had cirrhotic portal hypertension, 17 (30%) had portal vein thrombosis, 6 (11%) Caroli disease/Congenital Hepatic Fibrosis and 1 Nodular Regenerative Hyperplasia. Median admission values for platelets were 79 (7–407) x109/l, total bilirubin 14 (1–503) μmol/l, PELD score -1.4 (n = 53, range -6.7 to +43.5), MELD score 9 (n = 13, range 6–19). Management included octreotide in 62 (89%) and antibiotics within 24 h in 38 (54%). Endoscopy showed predominantly grade III (33 (47%)) and IV (21 (30%) esophageal varices. Endoscopic therapy was performed in 55 (79%). Post-AVB morbidity was identified in 39 (55%) episodes and in 29 (61%) of first AVB. Infection occurred in 19 episodes (27%), and in 15 (32%) of first AVB. Seven patients had bacteremia/occult bacteremia, 3 sepsis, 9 localized infections (1 aspiration pneumonia, 1 cholangitis, 1 liver abscess, 2 respiratory infections, 2 viral enteritis, 2 urinary infections). Incidence of infection did not change between eras 2000–04, 2005–09 and 2010–15. Median time to diagnosis of infection after AVB was 2 days (range 0–30). 13 (68%) patients had prophylactic antibiotics. Comparing the two groups, one with episodes of infection (inf+) and other with no infections (inf-), median length of stay was longer in inf+ (22 days (range 5–220)) compared to inf- (6 days (2–209)) Inf + were more frequently admitted in CCU (9 (47%) vs. 5 (10%)). One patient died in each group (inf+ 5% and inf- 2%). Infection was associated with severity of liver disease (PELD, Odds ratio 1.06, 95% CI 1–1.12, p
= 0.04) but not with age (p
= 0.07) or cause of portal hypertension (cirrhotic vs. non cirrhotic, p
Conclusion: AVB in children is associated with low mortality but significant morbidity, especially due to infections. Future studies are needed to examine the effectiveness of prophylactic antibiotics on admission and of primary prophylactic treatment of varices in reducing overall morbidity and infection rate.
175 THROMBOPHILIA PROFILE IN PEDIATRIC PATIENTS WITH CIRRHOSIS AND LIVER FAILURE FROM THE PEDIATRICS HOSPITAL AT THE WESTERN NATIONAL MEDICAL CENTER
Martha Midory Rodríguez Pérez, Yolanda Alicia Castillo de León, Ana Rebeca Jaloma Cruz, Juan Carlos Barrera de León, Roberto Garibaldi Covarrubias, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, Mexico
Introduction: The liver plays a central role in the hemostatic system. The coagulation system in patients with cirrhosis is in a state of rebalance between antihemostatic and prohemostatic factors. The observation of inherited thrombophilia (protein C deficiency, protein S deficiency, antithrombin III deficiency, mutation of factor V Leiden, gene mutation of prothrombin G20210A, polymorphism of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, and polymorphism of angiotensin converting enzyme (ACE-1) increase the risk of thrombosis of the portal vein in patients with cirrhosis. It is suggested that hypercoagulability may play a role in thrombosis of the hepatic artery after liver transplantation.
Objective: To characterize the profile of thrombophilia of pediatric patients with cirrhosis and liver failure at the Hospital of Pediatrics, Western National Medical Center.
Material and Methods: A study was conducted in pediatric patients, carriers of cirrhosis and liver failure at the Hospital of Pediatrics. Anticoagulant activity protein (protein C, protein S and antithrombin III) and factor VIII were determined by clotting assay. Mutations of thrombophilia panel, including factor V Leiden mutation, prothrombin gene mutation G20210AA, MTHFR C677T and A1298C polymorphisms, and polymorphism of angiotensin converting enzyme ACE-1 were determined by the technique of polymerase chain reaction.
Results: There were 25 children, 13 males, 12 females. The average age was 50.76 ± 46.96 (4–189) months. The main cause of cirrhosis was biliary tract atresia (72%). Distribution based on the Child-Pugh stadium was the following: stage A 24%, stage B 48%, and stage C 28%. It was identified protein C deficiency in 14 patients (56%), protein S deficiency in 3 patients (12%), antithrombin III deficiency in 9 patients (36%). Factor VIII elevated in 92% of the population was documented. The mutations were made only to 23 patients; the main identified mutation was polymorphism deletion ACE-1 in 8 patients (34.7%), the MTHFR C677T polymorphism was the second cause with 21.7%, MTHFR A1298C polymorphism in 8.6%, compound heterozygote of MTHFR C677T / A1298C in 17.3%.
Conclusions: It is considered that the deficiency of anticoagulant proteins and elevation of factor VIII is acquired secondary to chronic liver disease itself. The highest frequency of submission of ACE-1 may be due to the association of ACE-1 in metabolic processes of the liver and liver fibrogenesis participation.
∗176 EFFECTIVE GENERATION OF INDUCED PLURIPOTENT STEM CELLS FROM SMALL VOLUME PERIPHERAL BLOOD SAMPLES FOR IN VITRO MODELING OF PEDIATRIC LIVER DISEASES
Claudia Raggi, Massimiliano Paganelli, Marie M’Callum, Chenicka-Lyn Mangahas, Suleen Raad, Toan Quang Pham, CHU Sainte-Justine, Montreal, QC, Canada
Background: Induced pluripotent stem cells (iPSC) proved to be suitable for in vitro modeling of liver diseases. Although iPSCs can be generated by reprograming almost any somatic cell, skin fibroblasts are still the most widely used. Unfortunately, the need for skin biopsies complicates the feasibility of large studies with iPSCs in children.
Aim: To define reprogramming and culture conditions allowing an effective, reproducible generation of high quality iPSCs from small volume peripheral blood samples.
Methods: Peripheral blood mononuclear cells (PBMC) were isolated from blood samples, and expanded in vitro for 9 days in a conditioned medium to enrich the erythroblast population. Reprogramming was achieved using a Sendai virus carrying the four Yamanaka's factors. By day 14 post-transduction, iPSC colonies were identified through fluorescence live staining with anti-TRA-1–60 antibodies. Individual populations were seeded on vitronectin and expanded in Essential 8 medium, in physiological oxygen (4%) conditions. After 8 passages and the elimination of thermosensitive Sendai virus through 2 cyles at 39 C, the cells were analyzed for the expression of pluripotency-associated markers by real-time PCR, fluorescence immunostaining and flow cytometry. iPSCs were then differentiated to hepatocyte-like cells following a well-validated protocol (Si-Tayeb K, Hepatology 2010), with some modifications. iPSC-derived hepatocytes where assessed for the expression of markers and functions typical of mature hepatocytes, as we previously described (Paganelli M., Hepatology 2013).
Results: PBMC were obtained from 1.5 mL of peripheral blood drawn from 4 different subjects (0.5, 12, 16 and 37 years of age, respectively). Transduction with the Sendai virus led to the generation of 6.3 ± 5.6 TRA-1–60-positive colonies for each subject (0.22% ± 0.19% reprogramming efficiency). One population per subject was expanded under strict feeder-free and xeno-free culture conditions. Pluripotency markers (NANOG, OCT3/4, SOX2) were upregulated in all selected iPSC populations as compared to skin fibroblasts, and the expression was similar to H9 embryonic stem cells (p ns). Sox2, Nanog, Oct3/4, Tra-1–81 and SSEA were all strongly expressed in iPSCs at immunofluorescence. Single cell analysis by flow cytometry showed 86.1% (66.2–90.3 IQR) of triple-positive (SSEA4/TRA-1–81/Nanog) cells. Differentiation to hepatocyte-like cells was achieved with all tested populations (Cyp3A4 activity: 3.1 ± 0.5 fold increase v. undifferentiated iPSCs; urea synthesis: 3.2 ± 0.3 mg/dl/million cells).
Conclusions: The methods described above allow generating high-quality iPSCs from only 1.5 mL of peripheral blood in less than 6 weeks, facilitating the use of iPSC technology for disease modeling in newborns, infants and children. Furthermore, the use of a non-integrating virus and the respect of strict feeder-free and xeno-free conditions allow a much faster scale-up for any future therapeutic applications.
177 ETIOLOGY AND PROGNOSTIC FACTORS OF CHILDHOOD ACUTE LIVER FAILURE IN A CENTER IN MEXICO CITY.
M Vichido-Luna1, Erick Montijo-Barrios1, J. Ramírez- Mayans1, R. Cervantes-Bustamante1, F. Zarate-Mondragon1, J. Cadena-Leon1, M. Cazarez-Mendez1, E. Toro-Monjaraz1, M. Lopez-Ugalde1, A. Sanchez-Ortega2, C. Ordaz-Ortiz3,1Mexico City, Mexico,2Panama City, Panama,3Mérida, Yucatán, Mexico
Acute liver failure (ALF) is a rapidly progressive, potentially fatal clinical syndrome occurring in previously healthy children. PALF is defined as biochemical evidence of liver injury and coagulopathy not correctable by vitamin K with International Normalized Ratio (INR) ≥ 1.5 in the presence of hepatic encephalopathy (HE) or INR ≥ 2.0 regardless of presence or absence of HE.
The majority of studies on ALF were conducted in Europe, EUA and Japan. The etiology and prognosis in those countries are different from Mexico. Prognoses features are suggested in pediatric patients from develop countries but not in developing.
Aim: To determine the causes of ALF and the possible prognosis markers in a center in Mexico city.
Design: Retrospective case and controls study. One hundred pediatric patients with ALF were included from January 2001 to January 2016. Medical records were reviewed for demographic, laboratory and clinical data.
Results: 100 children (51 female), median age 60.6 months, range 192–1 month. 66 (66%) patients recovered spontaneously, 34 (34%) patients died without transplantation. Specific causes of ALF could be identified as infectious diseases 48% the most frequent Hepatitis A virus infection, immunologic diseases 10%, metabolic diseases 7%, toxic liver injury (paracetamol) 2% and indeterminate 33%. Conjugated hyperbilirubinemia, low albumin, high ammonia, and prolonged INR were associated with worse outcome. Hepatic encephalopathy results in a bad prognosis factor.
Conclusion: In developing countries Hepatitis A virus is the most common known cause of ALF. Conjugated hyperbilirubinemia, albumin levels, ammonia and severe coagulopathy may be prognostic value to predict outcome.
178 INITIAL TREATMENT OF AUTOIMMUNE HEPATITIS IN CHILDREN: NEORAL CYCLOSPORINE VERSUS PREDNISONE PLUS AZATHIOPRINE
Miriam Cuarterolo1, Mirta Ciocca2, Susana López1, Vicente López11, Maribé Araujo1, Fernando Alvarez3,1Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Ramos Mejía, Buenos Aires, Argentina,2Hospital Alemán, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina,3Hospital Sainte Justine, University of Montreal, Montreal, QC, Canada
Prednisone (PRED) plus azathioprine (AZA) is the conventional treatment for autoimmune hepatitis (AIH). The adverse effects related to steroids result in low tolerance and poor adherence.
Aim: To evaluate the outcome, and adverse effects in patients with AIH comparing one group receiving PRED plus AZA (G1) with a second group receiving Cyclosporine (CsA) (G2) as initial treatment, followed by low dose of PRED plus AZA after remission, in both groups.
Patients and Methods: This prospective randomized study consisted of consecutive patients < 18 years old with definite or probable diagnosis of AIH using the IAHG criteria. In children presenting with liver failure (LF) persisting after one week of treatment, were placed on a triple immunosuppressive regimen (TIT), adding PRED-AZA or CsA depending on which initial group they were assigned to. Patients who recovered from LF were switched back to their initial treatment scheme.
Results: Fifty patients were enrolled, G1:26, G2:24. Clinical and laboratory features were similar in both groups. Thirteen (26%) patients presented with LF (8 received TIT). All children recovered liver function, G1: 4,7 ± 4,8 weeks, G2: 5,8 ± 2,3 weeks (p < 0.4). Liver biopsies were performed in 37/50 patients (71%), no difference in inflammation or fibrosis was observed. Median time of follow-up was 32 months. The outcome was favorable in both groups, although remission was achieved earlier in G1 (p < 0.0081). The adverse effects observed during initial treatment until achieving remission (excluding those who received TIT) were: Cushingoid syndrome, more frequently observed in G1 (p < 0.001) and gingival hypertrophy (p < 0.001) more commonly observed in G2. There was significant increase of the body mass index (BMI) in all patients since initial treatment until remission achievement (p < 0.001), however it was more important in G1. At one year of follow-up, 18 children presented mild cushingoid features, nine from each initial treatment group. Only two children were overweight in this period (BMI > 25), one from each group. No differences in height were found. Infectious events and adherence to treatment were similar in both groups.
Conclusion: Both therapeutic schemes were effective and safe. Remission was achieved earlier in G1. All patients presenting with LF recovered. Adverse effects were mild and transient in both groups. Significant BMI increase was observed during the initial period of treatment to remission, mainly in G1. In the maintenance period, despite receiving low doses of steroids, all patients showed a tendency to increase BMI.
179 DIAGNOSTIC DETERMINATION SYSTEM FOR HIGH-RISK SCREENING FOR INBORN ERRORS OF BILE ACID SYNTHESIS: RESULTS AND RECENT TREND
Nakayuki Naritaka1, Mitsuyoshi Suzuki1, Hajime Takei2, Huey-Ling Chen3, Kyung Mo Kim4, Seak Hee Oh4, Akihiko Kimura5, Takao Kurosawa6, Takashi Iida7, Hiroshi Nittono2, Toshiaki Shimizu1,1Juntendo University Faculty of Medicine, Tokyo, Japan,2Junshin Clinic Bile Acid Institute, Tokyo, Japan,3National Taiwan University Hospital, Taipei, Taiwan,4Asan Medical Center, Seoul, Korea,5Kurume University School of Medicine, Fukuoka, Japan,6Health Sciences University of Hokkaido, Hokkaido, Japan,7Nihon University College of Humanities and Sciences, Tokyo, Japan
Background: Some patients with cholestasis of unknown cause may have inborn errors of bile acid synthesis (IEBAS), leading to abnormalities of bile acid biosynthesis. Although many types of bile acid synthesis defects have been reported as this disorder, no detailed information on its incidence and other aspects in East Asia has been available. To elucidate the current status of IEBAS, we have conducted a high-risk screening using a diagnostic determination system over the past 21 years, between July 1996 and May 2016.
Methods: The target patients included children with hepatic disorders of which the cause could not be identified by conventional liver function testing or hepatitis virus testing, patients with liver cirrhosis of unknown etiology, sibling cases, and patients with cholestasis who exhibited serum levels of direct bilirubin (D-Bil) ≧2.0 mg/dL. Urine samples were sent to the Bile Acid Institute located in Tokyo, via refrigerated delivery service. From 2013, impregnated filter paper with sufficient urine volume (dried urine spots) were also start to be available. Urinary bile acids were analyzed via gas chromatography-mass spectrometry (GC-MS/MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS).
Results: Out of a total of 1,000 samples, 15 were differentially diagnosed with IEBAS, including 5 cases of 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase deficiency (2 in Japan, 2 in China, 1 in Thailand), 4 cases of 3-oxo-Δ4-steroid 5β-reductase deficiency (3 in Japan, 1 in Taiwan), 5cases of oxysterol 7α-hydroxylase deficiency (1 in Japan, 1 in Korea, 3 in Taiwan), 1 case of bile acid-CoA amino acid N-acyltransferase deficiency (speculated in Thailand). In Japanese cases, 2 cases of both 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase deficiency and 3-oxo-Δ4-steroid 5β-reductase deficiency were effectively treated with oral bile acid therapy. The third case of 3-oxo-Δ4-steroid 5β-reductase deficiency had spontaneous remission without oral therapy. The Japanese cases of oxysterol 7α-hydroxylase deficiency underwent successful liver transplantation.
Conclusions: Fifteen patients were identified with IEBAS in East Asia over the past 21 years. IEBAS is a rare, hereditary disease; therefore, increased cost and large amount of labor are required to make a definitive diagnosis via genetic analysis. The diagnostic determination system with urinalysis is considered useful for diagnosis and treatment planning, and furthermore, it contributes to improved treatment efficacy for IEBAS.
∗180 HEPATOCELLULAR INJURY IS MEDIATED THROUGH CASPASE 1/11 AND IL-1 RECEPTOR IN STEATOTIC LIVER UNDERGOING ISCHEMIA REPERFUSION INJURY
Vasantha Kolachala, Nitika Gupta, Sirish Palle, Ming Shen, Dmitry Shayakhmetov, Emory University School of Medicine, Atlanta, GA, USA
Background: A steatotic liver is increasingly vulnerable to ischemia reperfusion injury (IRI), which is commonly encountered during hepatic resection, shock, myocardial infarction and liver transplantation. After IRI, the steatotic liver develops exacerbated cell death and hepatocellular dysfunction but the underlying mechanisms leading to this response are incompletely defined. Caspases are endoproteases, which provide critical regulatory connections between cell death and inflammation and Caspase 1 is driven by the Inflammasome which are key signaling platforms that detect sterile stressors (DAMPs), releasing the highly pro-inflammatory cytokines interleukin 1β(IL-1β). Though an area of intense study, there is lack of literature on the role of Caspase 1 and the Inflammasome in steatotic liver injury.
Aim: To delineate the involvement of Inflammasome and Caspase 1 in mediation of exacerbated hepatocellular injury in steatotic liver undergoing IRI.
Methods: Male C57BL6/Wild-Type (WT) and Caspase 1/11 double KO and IL-1 receptor KO mice were fed a high-fat diet (HFD) for 12 weeks. Hepatic steatosis was determined by oil red O (ORO) staining. These mice were subjected to 40 minutes of ischemia followed by 2–24 hours of reperfusion. Hepatocellular injury was assessed by propidium iodide (PI) staining, histopathologic cell death scoring and serum ALT. Pro-inflammatory cytokines were measured by 20-Plex Luminex assay, and levels of Caspase 1, IL-1β and NLRP3 were quantified by RT PCR.
Results: Mice fed a HFD diet showed significant increase in body weight (42 ± 1.2, vs.24.6 ± 0.6 grams; p < 0.0001) and presence of hepatic steatosis by ORO stain. Significant increase in pro-inflammatory cytokines (IFNγ, IL-1α, IL-1β, IL-6 and IL-17) was seen in HFD fed mice undergoing IRI, suggesting a pro-inflammatory milieu in HFD IRI. RT- PCR demonstrated significant increase in levels of Caspase 1, IL-1β, and NLRP3 levels in HFD IRI at 2 hours of reperfusion. In addition, genetic deletion of Caspase 1/11 and IL-1R demonstrated significant reduction in serum ALT (WT IRI 935.6 ± 80 vs. Caspase 1/11 KO 435 ± 134.5 IU/l, p < 0.01 and IL-1 receptor KO 331.8 ± 96 IU/l, p < 0.003. Histopathologic cell death score for WT HFD IRI was 22.7 ± 2.4 vs. Caspase 1/11 KO 5.6 ± 1.38, p < 0.0002, IL-1R: 7.3 ± 2.2, p < 0.0008. In contrast, HFD fed AIM2 KO and AIM2/NALP3 double KO mice did not show any protection from liver injury and had high serum ALT.
Conclusion: Steatotic liver undergoing IRI is associated with elevation of the highly pro-inflammatory cytokine IL-1β, and shows protection from cell death in HFD fed Caspase 1/11 and IL-1R KO mice. On the contrary, no protection from cell death was seen in HFD fed AIM2/NALP3 KO mice suggesting a novel mechanism of injury in a steatotic liver involving Caspase 1 but independent of AIM2/NALP3.
181 FACTORS PREDICTIVE OF AN OBSTRUCTIVE PATHOLOGY AMONG FILIPINO INFANTS WITH NEONATAL CHOLESTASIS
Novette Regina M. Lagunzad, Germana V. Gregorio, University of the Philippines - Philippine General Hospital, Manila, Metro Manila, Philippines
Background: It is important to determine the etiology of jaundice in infants to avoid delay in management. There is presently no local study that has identified the features of infants predictive of an obstructive type of neonatal cholestasis.
Objective: To determine factors predictive of obstructive neonatal cholestasis among Filipino infants and to describe their outcome.
Methodology: The study is a retrospective and prospective cohort done at a local tertiary hospital. Jaundiced infants within the first 8 weeks of life who underwent percutaneous liver biopsy were included. Excluded were those with cholestasis secondary to metabolic or infective cause. Retrospective chart review (2009–2012) and prospective recruitment of patients (2013) were done. Factors investigated were the following: clinical (sex, family history of idiopathic neonatal hepatitis, maternal age at birth, order of birth, low birth weight, prematurity, type of feeding at onset of cholestasis, age at onset of cholestasis [<15 or >/ 15 days old], persistently pale yellow/ acholic stools, high-grade hepatomegaly and splenomegaly), biochemical (total bilirubin >10 mg/dL, direct bilirubin >7 mg/dL, aspartate serum transaminase >300 IU/L, alkaline phosphatase >200 IU/L, prothrombin time >/ 4 seconds off from control and GGT >/ 300 IU/L), and ultrasonographic factors (normal, hepato- and/ or splenomegaly, contracted/ absent gall bladder, ascites, and liver parenchymal liver disease). A final diagnosis of non-obstructive or obstructive neonatal cholestasis was made using histology and/ or operative cholangiogram as gold standard. Outcome was assessed on the 6th and 12th month from diagnosis as alive (well or with liver disease) or died. Crude odds ratio for obstructive jaundice was computed. Multiple logistic regression on significant variables was done (p < 0.05). Minimal computed sample size is 222.
Results: 263 patients were included: 161 with non-obstructive and 102 with obstructive cause (95 with biliary atresia; 7 with sclerosing cholangitis). Mean age at first consult was higher in those with obstruction [3.95 (SD 3.06) months vs. 2.59 (SD 1.55), p < 0.001]. On univariate analysis, obstruction was associated with females, pale yellow/ acholic stools, high-grade hepatomegaly and splenomegaly on palpation, GGT >/ 300 IU/L, and hepatomegaly on ultrasound. On logistic regression (Table 1), females (OR: 2.3), no family history of idiopathic neonatal hepatitis (OR: 1/0.25 or 4) and pale yellow/ acholic stools (OR: 13) were predictive of obstruction. 85% of patients with non-obstructive cause are alive and well while 80% of patients with obstruction have died.
Conclusion/Recommendation: Among jaundiced infants, females, no family history of idiopathic neonatal hepatitis and pale yellow/ acholic stools are predictive of obstruction. These infants had poor outcome. Prompt referral to a specialist is needed for any jaundiced infant with abnormal stool color.
182 ACUTE LIVER FAILURE OF AUTOIMMUNE ETIOLOGY IN CHILDREN AND ADOLESCENTS OF A PEDIATRIC INSTITUTION IN BRAZIL
Paula Rigo, Cristian Victoria Borges, Gilda Porta, Thais Tristao, Julia Almeida Ferreira, Gabriel Benevides, Irene Kazue Miura, Adriana Porta, Renata P S Pugliese, Vera L B Danesi, Juliana De Assis Do Carmo, Marcela Seoane, Children's Institute - Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil
Introduction: Autoimmune hepatitis (AIH) is a rare entity of liver chronic disease. The clinical spectrum is wide, may be acute, acute severe (fulminant), insidious or asymptomatic. An acute severe (fulminant) presentation, characterized by the development of hepatic encepha- lopathy within 26 weeks of the discovery of the disease, rarely has been described in children in South America. Corticosteroid therapy can be life-saving, but its use in the fulminant presentation of AIH (AIH-FHF) remains controversial.
Aim: To describe features of children diagnosed as having AIH-FHF and to describe the outcome of patients treated with immunosuppressive drugs.
Methods: Retrospective analysis of a collected database identified children and adolescents presented with AIH-FHF from 2000 to 2015 and followed up at the Liver Department of the Children's Institute of the University of São Paulo. AIH was diagnosed based on positive autoantibodies, raised immunoglobulin G, and histology when available. FHF were based in biochemical evidence of acute liver injury without previously recognised liver disease, with prothrombin time (PT) >15 sec or international normalized ratio (INR) > 1.5 not corrected by vitamin K, with clinical hepatic encephalopathy, or a PT > 20 sec or INR > 2.0 regardless of encephalopathy.
Results: 13 patients were identified with AIH-FHF being 12 (92.3%) patients classified as AIH type 2, one (7.7%) with AIH type 1. The average age was 30.5 months (range 12–171 m), 10 (76.9%) female. Since the onset of symptoms till the diagnosis the average time was 30 days (range 4–45 days). Among the 13 patients 10 (76.9%) were treated with methyprednisolone pulse therapy of whom 3 (30.0%) required liver transplantation, while all 3 (23%) untreated patients required LT. Untreated patients with methylprednisolone (n = 3) demonstrated 39.6 (mean) PELD scores during the initial presentation. Among treated patients, no difference in PELD scores were observed between responders and failures (42.7 x 39). Despite 6 (46%) patients undergoing LT, death occurred to 50% of them. The total survival rate in AIH-FHF in our study was 61.5%.
Conclusion: The most important strategy for AIH-FHF is to diagnose and consider treatment with corticosteroids. Liver transplantation should be considered before the occurrence of complications that can occur in acute liver failure influencing morbidity of the patients.
183 OBJECTIVE MEASUREMENT OF EFFECT OF LIFE STYLE MODIFICATION THROUGH A MULTIDISCIPLINARY APPROACH ON NON-ALCOHOLIC FATTY LIVER DISEASE: A RETROSPECTIVE STUDY
Roopali Mittal, Candaca Marshall, Judith O’Connor, Jennifer Gamblin, Deidre Graham, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
Introduction: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. NAFLD can progress to advanced liver disease. The most common etiology of NAFLD is related to obesity. Currently there is no specific treatment for NAFLD/NASH but evidence supports a role for dietary modification and exercise. A multidisciplinary approach has been reported to stabilize mean BMI and improving aminotransferase levels at 1 year follow-up in obese children with NAFLD.
There have been no studies in Oklahoma exploring the efficacy of lifestyle measures and multidisciplinary approach for NAFLD.
Aim: The purpose of this retrospective chart review is to objectively measure the effect of lifestyle modification through multidisciplinary approach on NAFLD in children followed in the Pediatric Hepatology Clinic at OU Childrens Physicians. We will also investigate for association of a type I axis disorder and rate of improvement.
Methods: This is a retrospective chart review involving obese children (BMI ≥ 95th percentile) with NAFLD, 2–18 years old, seen in Pediatric Hepatology Clinic at OU Childrens Physicians. It will include all visits between June 2014 to June 2015 and August 2015 to Aug 2016. Data is being collected for age, ethnicity, weight, height, BMI, BP, triglycerides, cholesterol, HDL, transaminases, GGT, alkaline phosphatase and insulin levels at all the visits. In addition, time interval for first follow-up, number of visits in one year and associated behavioral disorders is also being recorded.
Prior to August 2015, families were provided instructions for healthy lifestyle and dietary habits without any set guidelines in place. A written protocol for dietary and behavioral modification “Healthy Lifestyle Screening” was implemented in August 2015. “Healthy Lifestyle Screening” form was completed by the patient's family at every visit to record compliance and progress. After August 2015, frequency of follow-up visits was also increased. A visit with a dietician and psychologist was also implemented with every follow-up after August 2015. In our study, we will compare data one year before and after the implementation of protocol.
Results are being analyzed statistically in the following age groups: 2–5 years old, 6–13 years old, and 14–18 years old. Descriptive statistics will be computed for all demographic and clinical variables for all study subjects. The time period of June 2014- June2015 and Aug 2015-Aug 2016 will define the retrospective control group and the current treatment groups, respectively. Comparisons of data between these groups will be made using appropriate statics tests.
Results: Total number of subjects in control group is 38,and 36 have been enrolled in current treatment group until now. Preliminary data collection has revealed a predominance of male gender (72%) in children with NAFLD at our center and 50% of subjects are Hispanic. Chart review is ongoing and final results are still pending.
184 THE DISTANT OUTCOME OF HEPATITIS C VIRUS INFECTION IN CHILDREN
Ryo Matsuoka, Ryusuke Nambu, Tomoko Hara, Division of General Pediatrics, Shin-ichiro Hagiwara, Seiichi Kagimoto, Saitama Children's Medical Center, Iwatsuki, Saitama, Japan
Background: The long-term natural history of hepatitis C virus (HCV) infection in children is not well known. With recent developments in HCV treatment, understanding natural histories of HCV infection are likely to become more important.
Patients and Method: We conducted a retrospective cohort review of the medical records of patients newly diagnosed with HCV infection and referred to Saitama Children'sMedical Center from April 1990 to March 2016. Only children with documented positive HCV-RNA and a minimum of 6 months follow-up records were included. Children ≥18 years at the time of diagnosis and those with incomplete medical records were excluded from the analysis. We defined the day of infection as the date of birth for those who were vertically infected and the date of first blood transfusion for those infected via a transfusion.
Results: A total of 34 children (23 boys and 11 girls) were enrolled. The median age at diagnosis was 7.7 years (0.6–17.9 years) and the median follow-up period was 9.8 years (1.9–19.8 years). All children were asymptomatic with no occurrence of liver cirrhosis and hepatoma. The routes of infection were vertically acquired (VAC) in 7 (20.5%) and transfusion acquired (TAC) in 27 (79.4%) children. Moreover, before 2000, the number of children with VAC was 1 (3.6%) and with TAC was 27 (96.4%); after 2000, the number of children with VAC was 6 (100%) and no children with TAC were noted. The genotype was identified for 22 children: 1 (4.5%) with genotype 1a, 16 (72.2%) with genotype 1b, 3 (13.6%) with genotype 2a, and 2 (9.0%) with genotype 2b. 9 children received treatment for HCV infection and all of them were treated with interferon alone. Following treatment, a sustained viral response (SVR) was achieved in 3 children, no sustained viral response (NVR) in 3 children, 1 child relapsed, and 2 children discontinued treatment because of side effects. Natural clearance of HCV-RNA was observed in 7 (20.5%) with a median age of 8.4 years (4.1–15.1 years). The median period for natural clearance was 4.9 years (3.3 - 6.5 years) from the time of initial infection. A liver biopsy was performed in 19 children at a median of 7.8 years (1.2–12.7 years) since the initial infection. Fibrosis staging was scored using METAVIR scoring and all children had mild fibrosis (F0–2). There was no noteworthy association between fibrosis and genotype, period of infection, or amount of HCV-RNA.
Conclusion: In this study, all were asymptomatic, HCV progression was gradual, and neither liver cirrhosis nor hepatoma developed. When applying treatment guidelines of HCV infections, it is important to refer to the natural history in children. We think that treatment for HCV infections in children should be conducted with caution considering unknown or distant side effects of the drugs because it is possible that the treatment will not be required. We are accumulating similar cases from a multicenter database in Japan and the results are awaited.
185 LABORATORY AND HISTOLOGICAL FEATURES OF EARLY BILIARY ATRESIA
Sanjiv Harpavat, Milton J. Finegold, Benjamin L. Shneider, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA
Introduction: While the natural history of biliary atresia (BA) has been generally well-characterized, there is little information about the disease's early period, i.e., in the first 30 days of life. In this report, we describe early laboratory and histological findings in infants with BA.
Methods: Subjects were included if they were born between 2007–2014 and diagnosed with BA at our institution. For each subject, first aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AP), gamma-glutamyl transferase (GGT), conjugated bilirubin (Bc), and unconjugated bilirubin (Bu) results were collected from the electronic medical record. In addition, for subjects receiving a liver biopsy before 30 days of life, liver and bile duct remnant tissue were analyzed. Bc ratios were calculated as (Bc/[Bc+Bu]), and Spearman's rank correlation coefficients (rs) were calculated to correlate laboratory results with age. Hematoxylin and eosin staining, cytokeratin 19 immunohistochemistry, and trichrome staining were used to study tissue samples.
Results: There were 65 subjects who fulfilled inclusion criteria, of which 43 were females (66%) and five had syndromic features (8%). The median age of first serum laboratory testing was 63 days (range 1–163 days). AST and ALT had a strong positive correlation with age (rs 0.77 and rs 0.79, respectively), and were within the laboratory upper limits of normal when tested before 20–30 days of life. AP and the Bc ratio had a weaker positive correlation with age, whereas GGT and Bc did not correlate with age. Bc always exceeded the laboratory reference interval, and Bc ratios were above 0.20 in all infants except one who was tested at five days of life. Six infants underwent liver biopsy before 30 days of life. All six infants showed signs of extrahepatic obstruction, including bile plugging, duct proliferation, and portal fibrosis. All six infants also had bile duct remnants lacking epithelial-lined lumens and replaced with fibrous tissue.
Conclusion: Early BA is characterized by normal AST and ALT levels despite histological findings of obstructive biliary disease. In addition, similar to later periods, early BA has elevated Bc levels, almost all Bc ratios exceeding 0.20, and evidence of bile duct obliteration. Clinicians should be aware of these results when evaluating young infants with cholestasis, to identify BA earlier, accelerate treatments, and potentially improve overall outcomes.
186 SYNCHRONIZED APOPTOSIS AND MITOCHONDRIAL DAMAGE OF HEPATOCYTES SEEN IN PATIENTS HAVING LIVER FAILURE
Seiichi Kagimoto, Shinichiro Hagiwara, Saitama Ryosuke Nambu, Tomoko Hara, Satoshi Tonezawa, Ryo Matsuoka, Hiroshi Kishimoto, Saitama Children's Medical Center, Saitama, Japan
Background: Organ failure including hepatic one can occur in patients having metabolic / mitochondrial diseases. Some show microsteatosis with no evidence of inflammation in liver biopsy specimen. The real mechanism for liver failure is still obscure partly because of the high hurdle of hemorrhagic diathesis due to lowered protein synthesis to perform biopsies. We seldom see evidence of apoptosis in most clinical samples though experimental models show massive cell death via necrosis and apoptosis. Cytochrome C, released from mitochondria, are sensitive marker for apoptosis. We examined liver specimens and sera obtained from children having hepatic dysfunction including organ failures.
Methods: We included 10 patients with acute encephalopathy, 3 with hemophagocytic syndrome, 2 with Reye syndrome, one having Pearson disease, and one with hepatic failure due to hepatitis B virus. Serum specimens for cytochrome C obtained at various timings. Cytochrome C was measured by electrochemiluminescence immunoassay. Sixteen specimens from the liver, one from the heart, and one from the brain were obtained in acute clinical stages or at autopsy. TdT uridine nick endlabelling (TUNEL) was applied for detecting apoptosis. Immuno-staining for cytochrome C in addition to conventional histological staining and electron microscopy was also applied for examination.
Results: Serum cytochrome C elevated in acute stages and showed correlation with ALT increase and Ca2+ decrease. Histologically marked accumulation of small fatty droplets and diffuse synchronized apoptosis signals in the livers of acute encephalopathy, Reye syndrome, and acute hepatic failure. This feature disappeared shortly, e.g., 2 weeks later. Their mitochondria were swollen, but not so prominent as Pearson's disease. Simultaneously, granular patterns of cytochrome C localized to mitochondria were lost. One with acute encephalopathy recovered by using cyclosporine A.
Conclusions: Apoptosis can occur in such cells as the liver, brain, or muscles simultaneously and diffusely. Serum cytochrome C reflect apoptosis in tissue damages. Apoptotic change and mitochondrial malfunction occur in the same cells simultaneously. To rescue mitochondria from apoptosis should be considered to treat organ failures. Cyclosporin A, which suppresses apoptotic process by blocking formation of mitochondrial permeability transition, was proved effective.
187 CONTROLLED ATTENUATION PARAMETER VALUES IN HEALTHY THAI CHILDREN
Voranush Chongsrisawat, Panida Swangsak, Sombat Treeprasertsuk, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Patumwan, Bangkok, Thailand
Background: The prevalence of non-alcoholic fatty liver disease (NAFLD) in children is increasing worldwide. The gold standard for diagnosis of NAFLD is liver biopsy which is prone to several complications. The controlled attenuation parameter (CAP) is an attractive method of assessing hepatic steatosis due to its noninvasiveness, simplicity, reproducibility, and high accuracy.
Aims: To determine the normal range of CAP values in healthy Thai children and to identify the association of demographic, anthropometric parameters and body fat percentage with CAP values.
Methods: Children attending an elementary school in Bangkok were enrolled. Subjects with current or a history of liver disease were excluded. Overweight and obesity were defined according to the 2007 WHO child growth references. Body fat percentage was measured with bioelectrical impedance analysis using a body composition analyzer (Tanita®, BC-418). A FibroScan® 502 machine equipped with an M probe (Echosens, Paris, France) was used to capture CAP values.
Results: The mean age of the 531 recruited children (282 boys and 249 girls) was 8.8 years. In all 25% of these children were overweight and 18.3% obese. Boys had significantly higher body mass index (BMI) and body fat percentage than girls (18.9 ± 3.9 vs. 17.6 ± 3.3 kg/m^2, p < 0.001 and 22.3 ± 11.6 vs. 20.0 ± 7.6 percent, P p < 0.01, respectively). The mean CAP value was 181.2 ± 32.9 dB/m (5th -95th percentiles 130.0–235.4 dB/m). Boys had significantly higher CAP values than girls (185.6 ± 33.7 vs. 176.3 ± 31.2 dB/m, p
= 0.001). The univariate analyses with CAP as a dependent variable revealed that gender, age, weight, height, BMI, and body fat percentage were significantly associated with the CAP values (all p < 0.01). In a multivariate linear regression analysis, only BMI (β= 0.409, p < 0.001) and body fat percentage (β= 0.372, P p < 0.001) were independently associated with CAP values.
Conclusion: Normal range of CAP values in children was determined. Body mass index and body fat percentage were associated with the CAP values of the studied children.
188 THE TYPES OF LIVER PATHOLOGIC FINDINGS OD NON-ALCOHOLIC STEATOHEPATITIS IN KOREAN CHILDREN: SINGLE- CENTER STUDY
Yong Joo Kim1, Jung Min Yoon1, Se Min Jang2, Ja Hye Kim1,1College of Medicine, Hanyang University, Seoul, Korea2College of Medicine, KonYang University, Daejon, South Korea
Background: Histologically, non-alcoholic steatohepatitis (NASH) is divided into 2 groups, adult type (Type I) and pediatric-type (Type II). Severe steatosis, inflammatory cell infiltration in acinar zone 1 are histological features of Type II; on the other hand, weak steatosis, inflammatory cell infiltration in acinar zone 3 are features of Type I. We studied whether liver pathologic findings from children with NASH truly shows only children's type, not adult type.
Method: Liver biopsies were performed in 41 children of NAFLD of 7–15 years old in NASH was diagnosed in 35. We investigated the types of their pathologic finding, and whether there are any correlating factors of clinical and anthropometric data (height percentile, BMI percentile, obesity index, systolic blood pressure percentile, diastolic percentile) toward the trend for a specific pathologic typing.
Result: In 35 children, 19 patients (54%) were type I, 16 (46%) were type II. Type II was more numerous in ages 7, 9 and 15 years old, and the other age group showed more of type I. Among the clinical and anthropometric data, children with high BMI (>95 percentile) were noted in 81.25% of type II; hematocrit, albumin, and systolic blood pressure (SBP) percentile were significantly higher in type II (pvalue: 0.01, 0.005, 0.018, respectively). However, there was no correlation between NASH type and hypertension severity (p
= .310). Other clinical variables did not show statistically significant difference between the two types.
Conclusions: Not only pediatric-type NASH but also adult-type NASH was found in children. It might be meaningless that NASH ichildren would show children's pathologic findings.
Non-Alcoholic Steatohepatitis (NASH), Children, Liver biopsy, Pathologic finding
189 FEASIBILITY AND USEFULNESS OF SIMULTANEOUS MEASUREMENT OF LIVER STIFFNESS AND HEPATIC FAT DEPOSITION BY FIBROSCAN IN CHILDREN
Yuki Cho, Daisuke Tokuhara, Haruo Shintaku, Osaka City University Graduate School of Medicine, Osaka, Japan
Backgrounds and Aims: The aim of our study was to determine the usefulness and feasibility of transient elastography (FibroScan®) assessing liver stiffness and hepatic fat deposition without biopsy in children.
Methods: Obese children (Obese group BMI-SDS above 90th percentile) and non-obese children without liver disease (Control group) were examined for liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) simultaneously using Fibroscan®. The correlation between FibroScan results and clinical and biochemical data were analyzed with Pearson's correlation coefficient.
Results: A total of 244 patients (11.7 y ± 3.6 y, mean ± SD) including obese group (n = 71, 12.6 y ± 3.1 y) and the control group (n = 173, 11.4 y ± 3.8 y) were included. The CAP of obese group (290.5 ± 56.7 dB/m) showed significantly higher value than control group (185.5 ± 45.9 dB/m) (p < 0.0001). The LSM of obese group (5.6 ± 2.3 kPa) also showed the higher value than control group (4.0 ± 1.0 kPa) (p < 0.0001). In the obese group, the LSM correlated to CAP(ρ=0.548), age(ρ=0.407), AST(ρ=0.714), ALT(ρ=0.735), and APRI (ρ=0.761), and the CAP correlated to age(ρ=0.415), AST(ρ=0.442), ALT(ρ=0.457), and APRI (ρ=0.420), and BMI-SDS (ρ=0.532). On the other hand, in the control group, there is no correlation between FibroScan results and laboratory data.
Conclusions: Fibroscan® is a non-invasive tool to assess the liver stiffness and hepatic fat deposition simultaneously thus useful as a screening tool for nonalcoholic fatty liver disease especially in obese children.
∗190 SPECTRUM OF HEPATITIS IN DENGUE FEVER: DO ASPARATE AMINOTRANSFERASE LEVELS HELP IN GRADING SEVERITY OF DENGUE?
Ayesha Imran, Neelam Mohan, Deepak Goyal, Sakshi Karkra, Maninder Dhaliwal, Veenal Raghunathan, Medanta Medicity Hospital, Gurgaon, Haryana, India
Introduction: Dengue fever is a major health problem in many Southeast Asian countries. There is a paucity of data regarding the spectrum of dengue hepatitis in children.
Objective: We studied the profile of liver involvement in children with dengue fever and compared liver function tests in three categories of WHO dengue case classification.
Methods: Study design: Prospective study; Period: October 2013 to December 2014; serologically confirmed dengue patients were grouped into three categories: Group 1 - dengue without warning signs; Group 2 - dengue with warning signs (abdominal pain, persistent vomiting, fluid accumulation, mucosal bleeding, lethargy, liver enlargement, increasing hematocrit with decreasing platelets) and severe dengue (dengue with severe plasma leakage, severe bleeding or organ failure). Biochemical and clinical profile of hepatic involvement was studied. The comparison between groups for key outcome parameters has been done using standard normal deviation test (Z test); SPSS software has been used.
Results: One hundred and sixty two children with dengue fever (M:F – 2.37) were included in the study. Median age was 12 years (range 6 m–18 yrs). Hepatitis was observed in 151 (93.2%) patients. On comparing the various liver function tests (LFT) parameters among three groups, the difference in average serum bilirubin levels and Asparate Aminotransferase (AST) were significant in each group (p < 0.05). However, there was no difference in the average values of ALT and serum albumin levels among group 1 and 2 [p = 0.06 and 0.16 respectively]. Eight cases presented with Acute Liver Failure. Their median AST was 4817 (range 220–26,957); median alanine aminotransferase (ALT) was 2386 (range 176–11,100); median INR was 2.57 (range 1.6–4.2) and their median serum bilirubin was 2.95 (range 0.6 – 9.0). An AST of >3 times normal had a 61% PPV of falling in group 2 (Dengue with warning signs).
Conclusion: Some degree of hepatitis is very common in dengue infection with rise in AST being more than ALT irrespective of the severity of dengue. Of all liver function parameters, S. bilirubin and AST levels correlates best with severity of dengue infection. The new WHO classification of dengue correlates well with the degree of liver involvement. Severity of hepatitis correlates well with the severity of dengue and can help in triaging of dengue patients well. An AST value of >3 times the normal should warn the patient of the need for probable admission.
191 PRIMARY LIVER TRANSPLANT VERSUS TRANSPLANT POST KASAI IN BILIARY ATRESIA: WHICH IS BETTER?
Chhaya Kumari, Neelam Mohan, Sakshi Karkra, Deepak Goyal, Maninder Dhaliwal, Veenal Raghunathan, A Rastogi, S Goja, P Bhangu, V Vohra, S. Soin, Medanta Medicity Hospital, Gurgaon, Haryana, India
Introduction: Biliary atresia (BA) is the most common surgical cause of neonatal cholestasis. Kasai portoenterostomy, if done earlier, is successful. Most Kasai portoenterostomy patients eventually need liver transplant. Primary liver transplant for patients with BA is offered when there is delayed presentation or if features of significant liver dysfunction/cirrhosis is present at diagnosis.
Aim: To review experience of living related liver transplantation (LDLT) for BA, and to compare the outcome (Medical/surgical complications and survival) in patients who underwent LT with/without prior Kasai portoenterostomy (PE).
Methods: Prospectively collected data of living related donor liver transplantation in children from mid September 2004 to March 2016 were analyzed. The cases were divided into two groups: Group A - BA with previous Kasai PE; Group B: BA without previous Kasai PE. The short- and long -erm complications and survival were compared in both the groups.
Results: 190 LDLTs were performed during this period. There were total 68 BA patients of which 43 were post-Kasai. Children in the Group A - 43 (63%), mean age (40.6 months (5–15, 6 months)) with M:F ratio of 23:20 and mean weight 13.18 Kg (4.2–41 Kg) and Mean Pediatric End-Stage Liver Disease (PELD) scores of 18(7–37).13(30%) patients in this group were less than 1 year. In Group B 25 (37%), mean weight was 7.84 Kg (4.8–10.9) and mean age 14.6 months (4–65 months), 15 (60%) were less then 1 year and mean PELD 22.8 (11–37). In comparison to Group B, patients in group A had significantly more vascular complications and perforation (8(19%) biliary, 9 (24%) perforation,11 (26%) vascular complications (2 Hepatic Artery Thrombosis HAT, 9 Portal vein thrombosis PVT)) (p < 0.005). In group B, 2 had HAT and 2 (10%) had biliary leak with no perforation. Mean duration of stay was 29 days in Group A and 21 days in group B. Three died in Group A and 4 in Group B with overall survival of 93% and 84% respectively over a mean follow-up period of 3.76 years.
Conclusions: A previous Kasai-PE increases post-LT surgical complications such as portal vein thrombosis, bowel perforations and reexploration. Survival in < 1 year is significantly lower than >1 year. Post kasai patients seemed to have better survival than primary transplant group but there was no statistically significant difference in K+/K- < 1 year group. Post-operative surgical complications were seen more in patients who underwent transplant after Kasai procedure.
INFLAMMATORY BOWEL DISEASE
217 THE ASSOCIATION BETWEEN PEDIATRIC-ONSET INFLAMMATORY BOWEL DISEASE AND BONE MINERAL DENSITY IN ADULTHOOD
Amit Assa, Anat Guz Mark, Firas Rinawi, Raanan Shamir, Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center, Petach Tikva, Israel
Background: Inflammatory bowel disease (IBD) is known to pose a risk for low bone mineral density (BMD) in both children and adults. We aimed to evaluate the impact of pediatric-onset IBD on BND in adulthood.
Methods: Records of patients diagnosed with pediatric IBD were retrospectively reviewed. Patients who had documentation of dual energy X-ray absorptiometry (DXA) scans after the age of peak bone mass accrual (females-18 years, males- 20 years) were included. BMD was expressed as Z-score and defined as the lower between lumbar and femoral-neck BMD for each patient.
Results: 61 patients with pediatric-onset IBD were included. Median age at diagnosis was 15.3 years (IQR 14–16.5). Median age at first DXA scan in adulthood was 21.9 years (IQR 20.2–27.3). Mean BMD Z-score was -1.12 (± 1.04). Overall, 44.3% (n = 27) had osteopenia (BMD Z-score ≤-1), and 8.2% (n = 5) had osteoporosis (BMD Z-score ≤ -2.5). This deviation from normal distribution of BMD was statistically significant (p < 0.001). Bone status showed no correlation with age, disease severity, height z-score and vitamin D status at diagnosis, type of IBD or duration of disease. Significant correlation (r = 0.306, p
= 0.05), was identified between low weight Z-score at diagnosis and abnormal bone status in adulthood. Thirty-six patients had at least 2 DXA scans during follow-up. During a median interval of 3.6 years there was no significant change in BMD between first and last measurement.
Conclusions: Osteopenia and osteoporosis are frequent in adult IBD patients with pediatric-onset disease. BMD does not significantly change over time in these patients.
218 IMPACT OF AN IBD CAMP UPON DISEASE-SPECIFIC KNOWLEDGE AND QUALITY OF LIFE IN CHILDREN AND ADOLESCENTS WITH INFLAMMATORY BOWEL DISEASE
Andrew Day, Andrew McCombie, Richard B Gearry, University of Canterbury, Christchurch, New Zealand
Introduction and Aims: Residential camps for children and adolescents with Inflammatory Bowel Disease (IBD) appear to have numerous benefits, including enhancing peer support. This study evaluated the impact of a four-day camp for children with IBD in New Zealand, with particular focus upon disease-specific knowledge and quality of life.
Methods: Prior to New Zealand's first dedicated camp for children with IBD in January 2015, all campers were contacted and asked to participate in an evaluation of outcomes arising from the camp. Campers were asked to complete questionnaires regarding background disease status and demographic information, disease-specific knowledge (IBD-KID) and quality of life (IMPACT). Assessments were completed before the camp and then again one month and six months after the camp. The camp was based around adventure-based experiences and did not include specific IBD-related educational activities.
Results: Thirty-nine of 44 campers provided baseline information. The responders comprised 21 boys. Thirty-five were diagnosed with Crohn's disease and 4 with ulcerative colitis or IBD-unclassified. Median age of the campers was 14 years. At baseline, the average IBD-KID scores were 10.67 (±4), and median IMPACT scores were 133 (interquartile range 114.75–149.25). Mean IBD-KID scores increased from baseline at both 1 and 6 months (p 0.03 and p 0.04 respectively). One month after the camp, 58.1% of campers had improved disease knowledge while 64.3% had scores above baseline at 6 months. Similarly, 50% of children had improved QOL scores at 1 month. Although average QOL scores did not increase after 1 or 6 months, body image subscores (p
= 0.015) were increased at 6 months.
Conclusions: Children and adolescents with IBD attending this residential camp demonstrated enhanced disease-specific knowledge following the camp. These improvements in knowledge were maintained during the six months following the camp. These results demonstrate a further benefit of residential camps for these children and adolescents.
219 COMPARISON OF GENOTYPE AND PHENOTYPE BETWEEN CAUCASIAN AND HISPANIC CHILDREN WITH INFLAMMATORY BOWEL DISEASE
Arathi Lakhole1, Chuan Hao Lin2, Patrice Pinardo3, Alexis Holmes4, Stacy Kahn5, Barbara Kirschner5, William DePaolo2,1Children's Hospital Los Angeles, Los Angeles, CA, USA,2Children's Hospital Los Angeles, Los Angeles, CA, USA,3University of Southern California, Los Angeles, CA, USA,4Rutgers University, New Brunswick, NJ, USA,5University of Chicago, Chicago, IL, USA
Background: Inflammatory bowel disease (IBD) is a chronic inflammation of intestinal tract caused by an interplay of genetics, environment and microbiome. Most of the studies in inflammatory bowel disease including large genetics studies for susceptibility and large clinic trials for drugs used in IBD were conducted in areas where minority population were underrepresented. Incidence of IBD in Hispanics is rising as this population is becoming the fastest growing minority population in US. NOD 2 mutations are associated in Crohn's disease in Caucasians but significance of this genetic variation in Hispanic population in United States is not known.
We hypothesize that differences exist between Hispanic and Caucasians children with inflammatory bowel disease, specifically disease presentation, clinical course and genetics.
Method: We conducted a multicenter study (Children's Hospital Los Angeles and University of Chicago) on Hispanic and Caucasian children with IBD to describe phenotypic and genotypic differences (NOD2 polymorphism). We also analyzed the frequency of NOD 2 mutation in control samples. DNA extraction was done using buccal swabs and SNP polymorphism using quantative PCR technique for two common CD-associated NOD2 mutations rs2066844 (R702W), rs2066845 (G908R).
Results: Total of 232 IBD patients were analyzed (African American- 29, Hispanic 43, Caucasian 135, other 15). Total of 100 controls were analyzed (African American- 6, Caucasian 9, Hispanic 82, and Other 3). Refer to Table 1 for details. Significantly higher number of males with Crohn's disease (CD) was seen in Hispanic (84%) as compared to females (15%), but the Caucasian population had equal distribution. No difference was seen in ulcerative colitis (UC) between males and females in these populations. UC was more common in Hispanics. CD was more common in Caucasians. In both Caucasian and Hispanic population age of diagnosis was highest in >10–17 years in CD and UC. Disease location in Crohn's disease in Caucasian was mostly ileocolonic (60%, 23% in Hispanic). In Hispanics, disease location was mostly colonic (54%, 17%) in Caucasians). Caucasians had more non-structuring non-penetrating type disease. Perianal disease was higher in Hispanic population compared to Caucasian. We also analyzed NOD 2 polymorphism R702W and G908R in CD and overall IBD patients and no difference in genotype frequencies was seen in Hispanic IBD patients and Hispanic controls (p value not significant).
Conclusion: There are significant difference in phenotypes between hispanic and Caucasian population, NOD 2 polymorphisms which are known susceptibility genes playing a role in IBD in Caucasians is not significant in Hispanic population. Thus, role of diet, environmental factors and socioeconomic factors as well as other susceptibility genes may play a role in Hispanic IBD etiology and progression.
220 BASELINE WALL THICKNESS IS LOWER IN MUCOSA-HEALED SEGMENTS 1 YEAR AFTER INFLIXIMAB IN PEDIATRIC CROHN'S DISEASE PATIENTS
Ben Kang, Yon Ho Choe, So Yoon Choi, Sangah Chi, Yaeji Lim, Tae Yeon Jeon, Samsung Medical Center, Seoul, South Korea
Backgrounds: Magnetic resonance enterography (MRE) has emerged as a valuable tool in diagnosing and monitoring treatment responses in Crohn's disease. We aimed to quantitatively investigate the therapeutic response to combined immunosuppression treatment by magnetic resonance enterography (MRE) in active luminal Crohn's disease in the pediatric population.
Methods: Pediatric patients with moderate-to-severe luminal Crohn's disease who received scheduled infliximab and azathioprine were included in this preliminary study. Ileocolonoscopy and MRE were performed at baseline and at 1 year, and Simple Endoscopic Score for Crohn's disease (SES-CD) and Magnetic Resonance Index of Activity (MaRIA) scores were calculated. The correlation between SES-CD and MaRIA scores were investigated with analysis per-person and per-segment.
Results: A total 167 segments from 17 patients were evaluated by both ileocolonoscopy and MRE. SES-CD and MaRIA scores showed significant correlations on both per-person analysis (ρ=0.699, P < 0.001), and per-segment analysis (ρ=0.596, P < 0.001). Analysis according to ileocolonic location of each segment revealed that correlation strength was strongest in the right colon (ρ=0.653, P < 0.001), while the correlation in the rectum was statistically insignificant (ρ=0.29, P = 0.096). Comparative analysis of MaRIA components revealed a significantly thinner bowel wall thickness at baseline in endoscopically healed segments (50/65) compared to unhealed segments (15/65) (median 4.3 vs. 7.2 mm, P = 0.036).
Conclusion: Therapeutic response to combined immunosuppression at 1 year assessed by MRE correlates with ileocolonoscopy in pediatric patients with Crohn's disease. Bowel wall thickness of the involved segments at baseline may affect treatment response to combined immunosuppression.
221 ASSESSMENT OF IMPACT III WELL-BEING DOMAIN SCORES IN ADALIMUMAB-TREATED PAEDIATRIC PATIENTS WITH CROHN'S DISEASE
Amy Grant1, Anthony Otley1, Johanna Escher2, Jeffrey S. Hyams3, Jen-Fue Maa4, Gabriela Alperovich4, Andreas Lazar5, Anne M. Robinson4, Anthony W. Wang4, Samantha Eichner4,1IWK Health Centre, Halifax, Nova Scotia, Canada,2Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands,3Connecticut Children's Medical Center, Hartford, Connecticut, USA,4AbbVie Inc., North Chicago, IL, USA,5AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany
Background: We assessed the impact of adalimumab (ADA) treatment on the well-being domain from the recently restructured IMPACT III questionnaire in patients (pts) enrolled in the IMAgINE 1 trial. The effect of ADA on emotional and social functioning domains has been reported previously.1
Methods: In IMAgINE 1, 6–17 years old pts with moderate to severe CD (baseline [BL] PCDAI >30) who failed or were intolerant to conventional therapy received ADA for 52 weeks (wks).2 Escalation to blinded weekly (EW) ADA was allowed after wk 12 for pts with disease flare/non-response followed by open-label (OL) EW ADA for continued flare/non-response. Pts ≥10 yr at BL received the IMPACT III questionnaire; each individual question has five Likert response options (0–4); scores are then linearly transformed to a range of 0 to 100 for ease of data interpretation, with higher scores representing better HRQoL. Changes from BL in the well-being domain score and in individual IMPACT III questions at wks 12, 26, and 52 were reported. Prior infliximab exposure was used for subgroup analyses. Last observation carried forward (LOCF) was used for missing data (post-BL), pts who discontinued, or who moved to OL EW ADA.
Results: A total of 172 pts were analyzed: 55% were males, median PCDAI was 40, median CRP 1.2 mg/dL, and mean IMPACT III well-being score 46 at BL. 75 pts had prior exposure to infliximab. Mean well-being domain scores at BL for infliximab-naïve and experienced pts were 49 and 44, respectively. Statistically significant improvements in well-being domain and individual questions scores were observed from week 12 and maintained to week 52 (Table). Overall well-being domain score at wks 12, 26, and 52 was 69, 68, and 68, respectively. Numerically higher changes from BL in well-being domain scores were seen in infliximab-naïve pts compared with infliximab-experienced pts at wks 12, 26, and 52 (26, 27, and 25 vs. 18, 16, and 16, respectively).
Conclusions: ADA treatment was associated with significant improvements in HRQoL in children with CD. Increases in well-being domain scores and individual question scores were maintained up to week 52 regardless of prior infliximab exposure.
1. Grant et al. Poster presentation at the 2016 European Crohn's and Colitis Organisation Congress. [Abstract # A-1340]. Amsterdam, Netherlands March 16–19, 2016; 2. Hyams et al. Gastroenterol. 2012;143:365.
∗222 CLINICAL CHARACTERISTICS AND LONG-TERM SURGICAL RISK OF PEDIATRIC CROHN'S DISEASE: A SINGLE-CENTER EXPERIENCE
Hyun Jin Kim1, Kyung Mo Kim2, Seak Hee Oh2, Jin Min Cho3,1College of Medicine, Busan Paik Hospital, Inje University, Busan, Busan, South Korea,2Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, South Korea,3Seoul National University Bundang Hospital, Seongnam, South Korea
Background and Aims: Although pediatric Crohn's disease (CD) has a different phenotype and clinical course to adult CD, its clinical features and surgical risks are poorly defined, especially in Asian countries. The aim of this study was to investigate the clinical features and long-term surgical prognosis of pediatric CD in a Korean population.
Methods: We retrospectively analyzed 600 patients who were younger than 18 years of age at CD diagnosis between 1987 and 2013. Patient characteristics at CD diagnosis and clinical courses were analyzed.
Results: The male-to-female ratio was 2.4:1 and the median age at CD diagnosis was 14 years (range, 6 months to 17 years). A positive first-degree family history of inflammatory bowel disease was present in 30 patients (5%). Seventy patients (11.7%) showed a growth delay. The cumulative probabilities of perianal fistula at 1, 5, and 10 years after diagnosis were 50.1%, 54.7%, and 57.4%, respectively. The cumulative probabilities of anti-tumor necrosis factor treatment at 1, 5, 10, and 20 years after diagnosis were 10.9%, 26.6%, 42.3%, and 77.4%, respectively. The cumulative probabilities of intestinal resection at 1, 5, 10, and 20 years after diagnosis were 4.8%, 17.5%, 33.1%, and 63.7%, respectively. In multivariate analysis, complicated behavior at diagnosis was associated with an increased risk of intestinal resection.
Conclusions: Our study is the largest Asian pediatric study which applied the Paris classification to patients. The prevalence of perianal fistula at diagnosis was higher than other western studies. Biologics and immunomodulators had no impact on the surgery rate.
223 CELLULAR DISTRIBUTION OF INNATE LYMPHOID CELLS ON THE PEDIATRIC INFLAMMATORY BOWEL DISEASE
Ju Whi Kim1, Jin Soo Moon1, Yuna Chang1, Kyung Jae Lee1, Ahlee Kim1, Hye Young Kim1, Ju Young Chang2, Jae Sung Ko1,1Seoul National University College of Medicine and Hospital, Jongno-gu, Seoul, South Korea,2SMG-SNU Boramae Medical Center, Jongno-gu, Seoul, South Korea
Introduction: Innate lymphoid cells (ILCs) are effectors of innate immunity and regulators of tissue modeling. ILC subpopulations have a cytokine expression pattern which resembles that of the helper T cell subsets TH1, TH2, TH17 and TH22. ILCs have been classified into distinct groups based on their cytokine secretion. ILC1 produce IFN-¥ã, ILC2 secrete IL-5 and IL-13, and ILC3 produce IL-22 and IL-17. Recent studies have discovered the heterogeneity of ILCs in the gastrointestinal tract. It is not known well about the distribution of ILCs in the pediatric inflammatory bowel disease.
Methods: In an ongoing study, intestinal mucosal tissue samples were obtained from inflammatory bowel disease patients and control aged between 7 and 19 years, undergoing endoscopy for assessment of disease activity or diagnosis. After cell preparation, cell-surface fluorescence intensity was assessed by flow cytometric analysis for sorting ILC subpopulation. ILC related cytokines were also assessed with conjugated antibody by fluorescein isothiocyanate. Clinical manifestation including disease activity and pathologic finding were reviewed. We compared normal mucosal tissues with inflamed mucosal tissue.
Result: Biopsy samples were collected from 13 inflammatory bowel disease patients (11 Crohn's disease and 2 ulcerative colitis) and 3 controls. Total 26 intestinal tissues were obtained and subdivided into 3 groups, disease cecum (n = 7), normal cecum (n = 10), small intestine (n = 9). ILC1 and ILC3 were major population of intestinal mucosal tissue in this study sample and ILC2 were detected as a small proportion of ILC. The proportion of the ILC 1 was significantly increased in disease cecum than normal cecum (p < 0.05). Total ILC population was decreased in diseases cecum than normal cecum. Discordance between surface marker and cytokine expression were observed.
Conclusion: The proportion of the ILC1 subset was higher in inflamed intestinal mucosa. ILC1 subsets which produce IFN-g may contribute to the pathogenesis of gut mucosal inflammation. Our results further support the general importance of ILC in the pathogenesis of inflammatory bowel disease.
Acknowledgement: This study was supported by grants from Eisai Korea Inc., 2016.
224 ASSESSMENT OF PREPAREDNESS FOR TRANSITION FROM PEDIATRIC TO ADULT CARE IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE
Julie Eisenberg1, Michelle Cho2, Alan Schwartz1, University of Illinois at Chicago, Chicago, IL, USA,2Children's Hospital, Park Ridge, IL, USA
Objectives: Many pediatric patients with Inflammatory Bowel Disease are not well prepared for transition to adult care. While tools such as the Transition Readiness Assessment Questionnaire are available, no tool has been developed specifically for transition of care in IBD. In our study, we surveyed IBD patients to assess preparedness for transition from pediatric to adult care. We then developed a questionnaire specifically for IBD transition. We hypothesized there would be disparity based on age, race and/or socioeconomic/payor status.
Methods: A survey was given to patients 13–19 years with previously diagnosed Crohn's disease or ulcerative colitis, seen at Advocate Children's Hospital Park Ridge between January 2016 andMarch 2016. 18 questions were divided into 4 categories (Medications, Knowledge, Independence, Feelings about transition). A total of 34 surveys were collected. Age, ethnicity, insurance type, medications, procedures and physician global assessment were taken from patient charts. Scores were determined based on number of correctly answered questions, which were assumed to indicate greater readiness to transition. Cronbach's alpha was used to evaluate internal structure of the survey, looking at total and subscale analysis. Patient variables were then correlated with total score and subscores.
Results: One question was dropped from analysis as it did not contribute useful variance. Total scale using the remaining questions had good reliability with Cronbach's alpha of 0.66. Each subscale of questions also had good reliability (Meds 0.68, Knowledge 0.61, Independence 0.7). Only age was mildly correlated with total score (r 0.31, t (32) 1.85, one-tailed p
= 0.037). No patient variables were significantly associated with Meds subscore. Knowledge subscore was significantly higher in Crohn's (mean 7.6, sd 2.6) than UC (mean 5.1, sd 2.7, t (18.6) 2.56, p
= 0.019). Independence subscore was significantly higher with age (r 54, p < .001) and higher in non-white (mean 15.7, sd 3.5) compared to white pts (mean 11.0, sd 2.8, t (6.4) 3.04, p .02). These effects remained significant in a linear regression that included both as predictors (p .001 for each).
Conclusion: We developed a survey tool that demonstrated good interitem reliability in total and within three planned subscales. As expected, older age was correlated with overall readiness for transition scores; older patients were also more independent in managing their disease. While there was no discrepancy found based on socioeconomic/payor status, we found discrepancy based on disease type and ethnicity. Patients with Crohn's were more knowledgeable about their disease compared to UC, and non-white patients were more independent in management of disease compared to white patients. Future studies will be necessary to better understand these discrepancies and to identify any additional correlations. While we did not include the number of years since diagnosis, we expect this to also impact scores.
225 EVALUATION OF A NOVEL EDUCATIONAL TOOL IN ADOLESCENTS WITH INFLAMMATORY BOWEL DISEASE: THE NEAT STUDY
Karla K.H. Vaz1, Yue Zhang2, Lee A. Denson2, Kevin A. Hommel2,1Nationwide Children's Hospital, Columbus, OH, USA,2Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA,
Objectives: Approximately 65–88% of adolescents are nonadherent to treatment regimens. In pediatric Inflammatory Bowel Disease (IBD) medication nonadherence rates are 50–88% across medications. Improving education in patients with chronic diseases has been shown to improve coping and to improve adherence to treatment in adults with IBD. Therapeutic patient education (TPE) has been used in patients with chronic diseases to train patients in the skills of self-managing or adapting treatment to their particular chronic disease, and in coping processes and skills.
Methods: In this pilot, mixed-methods study we sought to evaluate the feasibility and effect of TPE with a new guide-The IBD Pocket Guide on medication adherence, IBD knowledge and transition readiness in adolescents aged 11–18 years. Medication adherence was monitored using a MedMinder® Pill Dispensing system. Participants who were <90% adherent during a 4 week run-in phase were randomized to either a usual care group or an educational intervention (EI) group. Participants were followed for an additional 4 weeks after intervention.
Results: Trends were found in the EI to suggest improved medication adherence as well as improved IBD knowledge. Patients in the EI group had significantly improved knowledge of osteoporosis (p
= 0.0476). Qualitative data showed that participants did not like the use of the large pillbox, but did perceive that they had improved knowledge after the educational intervention. Families and patients found the IBD Pocket Guide to be useful and informative as a succinct guide to IBD.
Conclusion: Therapeutic patient education may be beneficial for improving patient medication adherence and IBD knowledge. Future studies guided by these pilot results will recruit a larger number of patients to test for the anticipated differences between groups.
∗226 INTERNATIONAL VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE COHORT STUDY (NEOPICS): RESULTS FROM THE FIRST FIVE YEARS OF STUDYING VEOIBD
Karoline B Fiedler1,2, Aleixo M Muise1,2,1SickKids Inflammatory Bowel Disease Centre and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada,2Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada
Background: The incidence and prevalence of Inflammatory Bowel Disease (IBD) is rapidly increasing worldwide, particularly in infants and very young children. Very Early Onset (VEO) and infantile IBD often present and manifest uniquely: disease location, severity, (non) response to conventional therapy, and outcomes can be very different than what is seen in older-onset patients. Even within VEOIBD, there can be great heterogeneity in phenotype. Much still remains unknown about the causes, disease progression, and outcomes for VEOIBD patients – including how to best optimize existing and potential therapies. These differences within and in comparison to older cohorts may be best explained by regarding VEOIBD as many different diseases, each influenced strongly by various genetic pathways or monogenic causes.
Objective: The interNational Early Onset Paediatric IBD Cohort Study (NEOPICS) is a SickKids’ based initiative that brings together international pediatric gastroenterologists and academic scientists to identify and investigate the causes, and develop new treatments and cures for VEOIBD (www.neopics.org).
Methods: VEOIBD patients are consented by their local pediatric gastroenterologist, with de-identified data and family biological samples shipped to NEOPICS. Whole exome sequencing on Illumina Hi-Seq is done for all participants. Based on the individual's phenotype/genotype, additional genetic, functional, and/or microbial assays may be performed to validate and further examine candidate mutations. All clinically significant results are reported to the clinician and validated in a CLIA-certified lab.
Results: To date, 535 VEOIBD patients (59.0% male, age 3.8 ± 0.2 yr, 93.5% with colonic distribution) have participated in NEOPICS along with 315 relatives (263 trios) from 26 countries. With our collaborators, over 50 genes have been recognized as monogenic causes of VEOIBD. In NEOPICS, 26 clear genetic diagnoses have been made in patients from Canada, United States, Chile, Uruguay, China, Australia, New Zealand, Sweden, Israel, Ireland, Spain, Romania, and others. Seven new genes have been discovered including TTC7A, PLVAP, TRIM22, and NHE3, with 18 additional genes/pathways examined, and 36 organoids generated for further assays and future drug trialing. Four patients had successful bone marrow transplant with more now awaiting transplant; others have been advised against specific therapies due to genetic profile and predicted risks.
Discussion: VEOIBD are more likely genetic driven diseases, including monogenic causes, that vary widely in presentation and will require precision based medicine to identify and treat appropriately. There are also many young patients with no clear, disease-causing genetic or functional pathway despite complex disease. NEOPICS has had great success to date and a strong, international collaboration will be vital to continue to identify and investigate the causes, and develop new treatments and cures.
227 LESS COLONIC BUT MORE UPPER GASTROINTESTINAL AND PERIANAL INVOLVEMENT IN JAPANESE CIHLDREN WITH CROHN'S DISEASE: RESULTS OF JAPAN PEDIATRIC INFLAMMATORY BOWEL DISEASE REGISTRY
Katsuhiro Arai1, Reiko Kunisaki2, Fumihiko Kakuta3, Shin-ichiro Hagiwara4, Takatsugu Murakoshi5, Tadahiro Yanagi6, Toshiaki Shimizu7, Yoshiko Nakayama8, Takashi Ishige9, Tmoki Aomatsu10, Mikihiro Inoue11, Takeshi Saito12, Itaru Iwama13, Hisashi Kwashima14, Hideki Kumagai15, Hitoshi Tajiri16, Naomi Iwata17, Takahiro Mochizuki18, Atsuko Noguchi19, Toshihiko Kashiwabara20,1National Center for Child Health and Development, Tokyo, Japan,2Yokohama City University Medical Center, Yokohama, Japan,3Miyagi Children's Hospital, Miyagi, Japan,4Saitama Chindren's Medical Center, Saitama, Japan,5Tokyo Metropoitan Children's Medical Center, Tokyo, Japan,,6Kurume University School of Medicine, Fukuoka, Japan,7Juntendo University Graduate School of Medicine, Tokyo, Japan,8Shinshu University School of Medicine, Nagano, Japan,9Gunma University School of Medicine, Gunma, Japan,10Osaka Medical College, Osaka, Japan,11Mie University Graduate School of Medicine, Mie, Japan,12Chiba University School of Medicine, Chiba, Japan,13Okinawa Chibu Hospital, Okinawa, Japan,14Tokyo Medical University, Tokyo, Japan,15Jichi Medical University, Tochigi, Japan,16Osaka General Medical Center, Osaka, Japan,17Aichi Children'sHealth and Medical Center, Aichi, Japan,18Osaka Police Hospital, Osaka, Japan,19Akita University Graduate School of Medicine, Akita, Japan,20Yamagata Prefectural Central Hospital
Background: There is a few nationwide registry report from Asia for pediatric inflammatory bowel disease (IBD). This study aimed to reveal the characteristics of Japanese children with IBD, and compare them to that of Europe.
Methods: This is a prospective web-based registry study of newly diagnosed Japanese children with IBD. The Paris classification was used to categorize the feature of subjects. The results were compared to those of published EUROKIDS data.
Results: Between November 2012 and December 2015, 265 IBD children were registered from 20 institutions. After the exclusion of 22 cases for incomplete workup, 91 Crohn's disease (CD), 146 ulcerative colitis (UC), and 6 IBD-unclassified, were analyzed. For the age at diagnosis, 20.9%, 21.9% and 83.3% of CD, UC and IBD-U were categorized as A1a (<10 y), respectively. For the CD location, L1 (ileocecal), L2 (colonic), L3 (ileal and colonic), and L4 (upper intestinal) were 18.7%, 13.2%, 64.8%, and 54.9%, respectively. For the disease extent of UC, 76% had E4 (pancolitis) and 6.8% had E1 (proctitis). For the CD behavior, B1 (non-stricturing/non-penetrating), B2 (stricturing), B3 (penetrating), and B2B3 were 83.5%, 11.0%, 3.3%, and 2.2%, respectively. The comparison between two registries revealed less L2 (13.2%vs.27.3%, p < 0.05) and more L4a (47.3%vs.29.6%, p < 0.05) involvement as well as higher prevalence of perianal modifier in Japanese children (34.1%vs.9.4%, p < 0.01).
Conclusions: This study revealed similar results in age of diagnosis for CD/UC and disease extent of UC. However, there were less colonic but more upper gastrointestinal and perianal disease in Japanese CD.
228 THE PREVALENCE OF FUNCTIONAL ABDOMINAL PAIN DISORDERS IN PEDIATRIC PATIENTS WITH ESTABLISHED INFLAMMATORY BOWEL DISEASE
Kevin Watson, Miguel Saps, Sandra Kim, Brendan Boyle, Nationwide Children's Hospital, Columbus, OH, USA
Background: Patients with inflammatory bowel diseases (IBD) may have overlapping functional abdominal pain disorders (FAPDs) as a cause of underlying GI symptoms. The relationship between FAPDs and IBD has been well described in adults. However, there is a dearth of information on this overlap in children.
Objectives: 1) Describe the prevalence of FAPDs in pediatric patients with IBD in remission; 2) Describe the psychological profile of this group of children; 3) Assess the impact of the overlap of FAPDs and IBD on the child's quality of life.
Methods: This is a cross-sectional prospective study. Inclusion criteria: English speaking patients 8–18 years of age who were previously diagnosed with IBD. Disease activity was determined based on physician's global assessment, laboratory studies, and sPCDAI or PUCAI scoring. Children completed age appropriate validated questionnaires during GI clinic or infusion center visits including questionnaires to diagnose FAPDs (functional dyspepsia, irritable bowel syndrome (IBS), functional abdominal pain, abdominal migraine) according to the Rome III criteria (QPGS-III); Children Depression Inventory (CDI-2); State-Trait-Anxiety-Inventory for Children (STAIC-C2); and Pediatric Quality of Life-GI (Peds QoL-GI).
Results: 128 subjects were recruited; 81 (63%) fully completed the questionnaires. Those with incomplete questionnaires were excluded from the analysis. There were 36 females and 45 males with a mean age of 14.4 ± 2.6 years (62 with Crohn's disease [CD], 19 with ulcerative colitis [UC]). Seventy one patients (87.6%) were classified as being in remission. The prevalence of FAPDs in IBD patients in remission was 25.9% (17 CD, 4 UC; 95% CI, 20.6% - 79.4%), 14 females & 7 males with FAPD vs. 19 females and31 males without FAPD (p 0.0375). Children with FAPDs had IBS 13.6% (63.6% IBS-diarrhea predominant and 9.1% IBS-constipation predominant, 27.3% could not be further subcategorized), abdominal migraine 11.1%, functional abdominal pain 1.2%. Children with IBD and remission with and without FAPDs met criteria for anxiety 14.3% vs. 2% (p 0.0640) and depression 23.8% vs. 2% (p 0.0057) respectively. The average Peds QoL-GI score of children with IBD in remission with FAPDs was 71 vs. 86.5 (higher means better quality of life) in those without FAPDs (p 0.0077).
Conclusions: We found a high prevalence of FAPDs among children with IBD in remission. The prevalence found in our study is higher than the values found in the only two other published pediatric studies. This is the first study to systematically assess all FAPDs using the Rome III criteria and to demonstrate that this group of children has worse anxiety, depression and quality of life than children with IBD without FAPDs. The identification of the subgroup of patients that are predisposed to developing FAPDs may allow implementing early intervention strategies that could prevent or improve anxiety, depressive symptoms and poor quality of life.
∗229 UNCOVERING TRIPARTITE MOTIF CONTAINING 22 BINDING PARTNERS AND THEIR ROLES IN INFLAMMATORY BOWEL DISEASE.
Khalid Hossain, Aleixo Muise, Qi Li, Conghui Guo, Ryan Murchie, Neil Warner, The Hospital for Sick Children, Toronto, ON, Canada
Background: The severe multi-systemic phenotype of very early onset inflammatory bowel disease (VEOIBD) is often difficult to treat with conventional therapies. Although monogenic mutations of known genes have been identified, the majority of VEOIBD patients do not present with any known defect. Our recently published whole exome sequencing (WES) of VEOIBD patients and their parents identified autosomal recessive variants in the antiviral E3 ubiquitin ligase TRIM22, identifying and characterizing TRIM22's novel role in NOD2 signalling regulation through its direct interaction and ubiquitination of NOD2. The mutant forms of TRIM22 found within the patients exhibited aberrant NOD2 antiviral and pro-inflammatory signalling. TRIM22's implication in both antiviral and inflammatory pathways, and roles TRIM proteins play in proliferation and apoptosis, inspires confidence in its critical role in VEOIBD patients. However, the complete range of pathways influenced by TRIM22 remains a mystery. We hypothesize that TRIM22 lies at a crossroad of multiple cellular pathways related to inflammatory disease phenotypes. We propose to validate TRIM22 binding partners and uncover novel pathways with clinical implications in patients with severe VEOIBD.
Method: BioID, a method by which the protein of interest is fused with a promiscuous biotin ligase (BirA∗), was used to identify candidate binding partners of TRIM22. Proximal proteins were biotinylated by the TRIM22-BirA∗ fusion and were identified by biotin affinity capture and mass spectrometry. Co-immunoprecipitation (co-IP) and immunofluorescent co-localization were used to validate these potential binding partners of TRIM22.
Results: Co-IP demonstrates TRIM22 interaction with histone deacetylase 1 (HDAC1), a component of the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex involved in cell growth and apoptosis. TRIM22 may associate with interferon regulatory factor 8 (IRF8) based on co-IP with supporting immunofluorescent co-localization in the cytoplasm near the nucleus. Co-IP suggests TRIM22 may also interact with nuclear pore scaffold Nup153, a protein involved in host-virus interaction and selective nuclear entry of proteins and mRNAs.
Conclusion: Candidate TRIM22 binding partners revealed by BioID include multiple proteins of the Mi-2/NuRD complex, genes linked with primary immune deficiency including cyclin T1 and its associated kinase (CDK9), locations of host-virus interaction, regulators of NOD2 signal regulation (e.g., PML), and genes within known inflammatory bowel disease loci. This research is currently validating these BioID-derived associations while confirming co-IP of TRIM22 with HDAC1, IRF8, and Nup153. Our patient WES database can be interrogated for novel disease causing mutations within TRIM22 pathways unveiled by these interactions, providing the potential for future therapies for phenotypes typically unresponsive to current treatments.
230 ASSESSMENT OF PEDIATRIC GASTROENTEROLOGISTS’ PERCEPTIONS AND PRACTICES REGARDING VENOUS THROMBOEMBOLISM PROPHYLAXIS IN PEDIATRIC INFLAMMATORY BOWEL DISEASE
Kimberley Chien, Hoda Hammad, Linda Gerber, Sujit Sheth, Robbyn Sockolow, Nicole Kucine, Weill Cornell Medical College, NY, NY, USA
Background: The risk of venous thromboembolism (VTE) is increased in children with Inflammatory Bowel Disease (IBD). This complication can have significant medical consequences and can lead to major morbidity and sometimes, mortality. While adult IBD guidelines recommend VTE prophylaxis in IBD patients, there are no similar guidelines for pediatrics and practice regarding prevention of VTE in pediatric IBD is variable. In this study, we sought to assess the opinions of pediatric gastroenterologists regarding VTE risk and prophylaxis practices in pediatric IBD patients.
Methods: An electronic survey of 21 questions regarding pediatric gastroenterologists’ knowledge of VTE and prophylaxis practices in IBD patients was created using REDCap, a secure web application for survey and data management. The survey was distributed to members of NASPGHAN via e-mail in three instances over a three-month period. Survey participants’ responses were collected in REDCap database and analyzed by Fisher's exact test and Chi-square test.
Results: Survey response rate was 9.3%. 92% of participants agree that pediatric IBD patients have an increased risk of VTE, but only 1/3 of respondents reported providing prophylaxis to their IBD patients. The most common setting for providing prophylaxis was in hospitalized patients with an IBD flare; mechanical and pharmacologic methods were used with equal frequency. For those practitioners who do not initiate VTE prophylaxis, the most commonly cited reason was lack of pediatric literature, with risk of bleeding, lack of education, and patient resistance reported as additional concerns. Thrombophilia evaluation was also addressed and most respondents did not feel that hematologic investigation was required.
Conclusions: Our findings demonstrate that pediatric gastroenterologists are aware that pediatric patients with IBD have an increased risk of VTE. However, despite this recognition, most practitioners are reluctant to start VTE prophylaxis for a number of reasons, with the primary reason reported as lack of literature. Despite limited response rate, these results bring forth important concerns among pediatric gastroenterology practitioners that prevent them from providing potentially life-saving VTE prophylaxis to children with IBD. This study also highlights the need for further investigation so that we can better understand the nature of VTE in pediatric IBD, guide pediatric gastroenterologists as they care for their pediatric IBD patients, and ultimately improve patient outcomes in pediatric IBD.
∗231 CANNABINOID RECEPTOR 2 ACTIVATION AMELIORATES INFLAMMATION IN MURINE MODEL OF CROHN'S DISEASE
Kristina L. Leinwand1, Colm B. Collins1, Ashleigh A. Jones2, Paul Jedlicka1, Soumita Ghosh3, Ruin Moaddel3,1Children's Hospital Colorado/University of Colorado School of Medicine, Aurora, CO, USA,2University of Colorado School of Medicine, Aurora, CO, USA,3National Institute of Health/National Institute on Aging, Bethesda, Maryland, USA
Background: Expanding marijuana legalization has generated vast interest in its therapeutic use in human disease. Limited scientific evidence suggests that marijuana use may have a positive symptomatic effect on inflammatory bowel disease (IBD) patients due to its analgesic and anti-inflammatory effects. However, our lack of understanding of how cannabinoids impact disease outcomes has prompted us to investigate the roles of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors in preclinical chronic IBD models. The CB1 receptor is preferentially associated with central nervous system functions while the CB2 receptor is found primarily on immune cells, including CD4 T cells, key regulators of intestinal inflammation. Furthermore, IBD is associated with upregulation of CB2 receptor in the inflamed intestines. Nevertheless, there remains a significant gap in our knowledge of how activation of CB1 and CB2 receptors will affect intestinal inflammation.
Methods: TNFΔARE mice express elevated TNF protein leading to Crohn's-like spontaneous ileitis and discontinuous transmural inflammation. In our study, wild-type (WT) and inflamed TNFΔARE mice were treated for two weeks with either CB1 agonist WIN55,212–2 or CB2 agonist Gp1a, and the ileitis was evaluated by PCR, flow cytometry, and blinded scoring by a pathologist. We also quantified intestinal endocannabinoids by HPLC, measured CB2 expression on regulatory T cells, and evaluated regulatory T cell suppressive function upon CB2 receptor activation.
Results: The endocannabinoid anandamide was induced in ilea of TNFΔARE mice (27 pmol/g) relative to WT (18.8 pmol/g; p < 0.05). In addition, CB1 receptor expression increased 3-fold (p < 0.0001) while CB2 receptor expression increased 19-fold (p < 0.01) in TNFΔARE as compared to WT mice. Unexpectedly, CB1 activation with WIN55,212–2 exacerbated intestinal inflammation and demonstrated increased expression of pro-inflammatory Th1 cells in the ileal lamina propria (p < 0.01). In contrast, CB2 activation with GP1a significantly decreased intestinal inflammation as demonstrated by reduced Th1 infiltration (p < 0.01) and improved histologic scoring (p < 0.05). Additionally, CB2 receptor expression is preferentially increased on regulatory T cells versus T effector cells, up to 2-fold in WT (p < 0.05) and up to 11-fold in TNFΔARE mice (p < 0.001). Moreover, CB2 receptor agonism led to a decrease of 7% in T effector cell proliferation due to improved suppressive function of regulatory T cells (p < 0.01). Lastly, CB2 receptor agonism increased concentration of anti-inflammatory cytokine IL-10 (vehicle 123 pg/mg, Gp1a 253 pg/mg; p < 0.05).
Conclusion: While CB1 receptor activation aggravates intestinal inflammation, CB2 receptor agonism attenuates murine ileitis through improvement in regulatory T cell suppressive function. Based on these findings, we would caution against the use of marijuana to treat IBD symptoms pending more comprehensive investigation in human disease.
232 AZATHIOPRINE IN PREVENTION OF ENDOSCOPIC RECURRENCE IN CHILDREN WITH CROHN'S DISEASE AFTER ILEOCECAL RESECTION
Kristýna Zárubová, Jiøí Bronský, Ondøej Hradský, Ivana Èopová, Lucie Poš, Richard Škába, Blanka Rousková, University Hospital Motol, Prague, Czech Republic
Objective: Ileocecal resection (ICR) is frequent type of surgery in patients with Crohn's disease (CD). Cumulative risk of surgery is growing with disease duration, so patients with CD, diagnosed in young age, have high risk to undergo intestinal surgery. The aim of this study was to evaluate endoscopic recurrence in children with CD, six months after ICR and also try to find potential risk factors.
Methods: In this study we prospectively observed children after ICR treated with azathioprine (AZA) in monotherapy or in combinatiton with aminosalicylates, endoscopy was performed in follow-up 6 month after ICR and was described by Rutgeerts score.
Results: Twenty one patients fulfilled inclusion criteria and finished 6 month follow-up. Eight patients had endoscopic recurrence (Rutgeerts score ≥ i2). Only potential risk factor found, was lower concentration of serum albumin at the time of surgery that was associated with higher endoscopic recurrence rate at 6 months (p = 0.042).
Conclusion: Endoscopic recurrence rate in children after ICR in our study is similar as in studies on adult patients. Albumin at the time of surgery could be potential predictor of disease recurrence. Supported by grants VZ FNM 64203/6001, GAUK 136215 and GAUK 246216.
233 QUALITY OF LIFE IN PEDIATRIC PATIENTS RECEIVING EXCLUSIVE ENTERAL NUTRITION IS EQUIVALENT TO CORTICOSTEROID THERAPY IN PATIENTS WITH ACTIVE INFLAMMATORY BOWEL DISEASE
Lara Hart, Camilla Halgren, Yasamin Farbod, Lawrence Mbuagbaw, Mary Zachos, Nikhil Pai, McMaster University, Hamilton, ON, Canada
Introduction: Inflammatory bowel disease (IBD) is a chronic illness that can affect a child's physical, social and psychological well-being. Studies have shown that active IBD is associated with lower quality of life (QOL) scores in children. Exclusive enteral nutrition (EEN) and corticosteroids (CS) are effective treatment options for induction of remission in pediatric Crohn's disease (CD), while CS is effective for induction of remission in ulcerative colitis (UC). EEN involves the use of a nutritional formula, via nasogastric (NG) tube or taken by mouth for 8 continuous weeks, however it is often poorly utilized due to perceived increased treatment burden for patients. Two studies have shown that QOL in children receiving EEN is significantly better at the end of therapy compared to baseline. However, no studies have assessed the effects of EEN therapy on QOL longitudinally during treatment, or against other IBD treatment options. The objective of this study was to compare longitudinal QOL scores in pediatric CD and UC patients receiving an 8-week course of EEN versus CS therapy.
Methods: This prospective cohort study involved patients 5–18 years old with IBD, followed up at McMaster Children's Hospital (Hamilton, Ontario, CANADA). Patients were included if they received EEN (Peptamen® 1.5) or CS therapy for induction of remission of moderate to severe CD or UC. All patients received 8 weeks of treatment. QOL was assessed using the KIDSCREEN-10 index. Clinical outcomes were assessed using the Pediatric UC Activity Index (PUCAI), or the modified Pediatric CD Activity Index (PCDAI). QOL and disease activity indices were assessed weekly during the 8-week induction therapy, and after 4 weeks of completion of therapy.
Results: Twenty-six patients were enrolled in the study. Fourteen patients received induction therapy with EEN (14 CD, 0 UC) and 12 with CS (4 CD, 8 UC). Among patients receiving EEN, 12 received therapy via NG tube, 2 refused NG tube insertion and received Ensure® orally. In CD patients, as PCDAI decreased, QOL significantly increased (r -0.43; p < 0.001). Similar trends were seen in UC patients; results did not reach statistical significance (r -0.25; p 0.245). Importantly, there was no significant difference in QOL between patients receiving EEN versus CS at each week of treatment, at 4 weeks post treatment, or overall (mean difference in QOL score 1.71; p
= 0.092, 95% CI,0.28–3.71).
Conclusion: Pediatric IBD patients receiving treatment for induction of remission experienced no difference in QOL on EEN therapy versus CS therapy. QOL in pediatric IBD is correlated with improvements in disease activity, not method of therapy used for induction of remission. Physicians and families should consider the benefits of EEN therapy and its superior side-effect profile when choosing therapy for induction of remission.
234 IS EARLY ONSET A RISK FACTOR IN THE OUTCOME OF CHILDREN WITH INFLAMMATORY BOWEL DISEASE?
Laura Villafane, Veronica Busoni, Daniel D’Agostino, Julieta Gallo, Juan Pablo Santino, Gaston Elmo, Marina Orsi, Hospital Italiano, Buenos Aires, Argentina
Introduction: Very early onset Inflammatory Bowel Disease (VEO-IBD) represents an exclusive form of IBD which is diagnosed in children younger than 5 years of age. It has been associated with increased disease severity, aggressive progression and poor responsiveness to most conventional therapies.
Aim: To evaluate if children with VEO-IBD show a different behavior after 5 years-follow-up compared to those pediatric patients with late onset.
Materials and Methods: Retrospective and transverse study in pediatric patients with IBD diagnosed from 1996 to 2010 at one reference center in Argentina. Diagnosis was established according to clinical presentation, laboratory, endoscopy, radiology and histology criteria. The variables considered were: median age, sex and location at diagnosis; severity, treatment requirements during follow-up and autoimmune diseases (AI) association. They were divided into 2 groups according to age in G1: younger than 5 years old and G2: older than 5 years of age.
Results: 147 IBD children (G1 50/147 and G2 97/147) were followed at a Pediatric Gastroenterology Unit. After 5 years follow-up or more: G1: n 29; 18/29 ulcerative colitis (UC) (62%), 7/29 (24%) Crohn's disease (CD) and 4/29 (14%) Unclassified IBD (U-IBD). G2: n 88 UC: 52 (59%), CD: 31 (35%) and UIBD: 5 (6%). Median age at diagnosis was G1: 2.8 years (SD: 1.3) and G2 8.3 years (DS: 5.2). Growth failure was seen in 3/29 in children in G1 vs. 24/88 in G2 (p
= 0.0605). All of them were treated with mesalazine. Patients with moderate disease, received immunomodulators as maintenance therapy. In G1 2/29 (7%) received biological therapy (anti TNFα) vs. G2 10/88 (11%) (p
= 0.4729). In G1 3/29 patients required colectomy due to failure to immunosuppresive medications vs. 6/88 in G2, 4 required ileocolonic resection due to stenotic or fistulizing behavior and two proctocolectomy. In G1 13/29 (45%) presented AI diseases (Celiac disease, AI hepatitis, sclerosing colangitis, rheumatoid arthritis) vs. 19/88 (21.5%) in G2 (p
= 0.0362). In G1: 1/29 required liver trasplantation due to cirrhotic evolution and in G2: 2/88 under azathioprine treatment developed myeloid leukemia and another presented a non-Hodgkin lymphoma.
Conclusion: According to this cohort, early onset did not represent a major risk factor, at least in the first five years of follow-up. The differences observed to previous published data may be due to genetics and /or local environmental characteristics in Latin America. More studies are necessary to shed light on the complex mechanisms involved in IBD outcome in childhood.
235 LONG-TERM EFFICACY AND SAFETY OF LOW DOSE THIOPURINE-ALLOPURINOL COMBINATION THERAPY (TP/AP) IN PEDIATRIC INFLAMMATORY BOWEL DISEASE (PIBD)
Lauren Jarchin, James Markowitz, Cohen Children's Medical Center of New York, Lake Success, NY, USA
PIBD patients are routinely treated with thiopurine drugs for maintenance therapy. In some, metabolic hypermethylation precludes successful therapy by promoting preferential production of inactive 6-methylmercaptopurine (6MMP) over active thioguanine nucleotides (6TG). This metabolism can be reversed by switching to a regimen of low dose thiopurine and concomitant allopurinol (Sparrow Alim Pharm Ther 2005). There have, however, been few studies in the pediatric population that address the long-term efficacy and safety of this approach.
Objective: To evaluate the efficacy and safety of low-dose TP/AP combination therapy in PIBD patients.
Methods: A retrospective single center chart review of all children who had thiopurine metabolite testing (Prometheus Labs) between 2005–2015 was performed to identify all who received TP/AP. Metabolite changes after TP/AP, and clinical efficacy as evidenced by ongoing or recurrent corticosteroid use, IBD-related surgery, or escalation in therapy (methotrexate or anti-TNF) were determined. Leukopenia, elevated AST or ALT, serious infection and malignancy were also recorded.
Results: 424 children had metabolite testing after initiating treatment with either 6-mercaptopurine or azathioprine monotherapy. Of these, 38 (9%) were switched to TP/AP. Incomplete records in 10 left 28 evaluable subjects (11 male, mean age 14 ± 4 yrs, 17 CD, 11 UC), including 1 who began TP/AP shortly after a bowel resection. Mean duration of TP/AP was 30.9 ± 25.2 mos. Prior to TP/AP, 6MMP levels were 8723 ± 6305 pmole/8X108RBC, with 18 (64%) subjects having 6MMP levels above the potentially toxic level of 5700 pmole/8X108RBC (range 6091–23555 pmole/8X108RBC). Baseline 6TG was less than the therapeutic target range of 230–400 pmole/8X108RBC in 17 (61%). After TP/AP, 6MMP was below the limits of detection in 25 (89%), while 6TG levels were >230 in 21 (75%, mean 339 ± 184 pmole/8X108RBC). Overall, 14/28 (50%) subjects were successfully maintained on TP/AP without additional steroids, biologics or surgery for a mean 27 mos (range 5–67mos). By contrast, 5 were steroid dependent, 3 were switched to methotrexate (after 3, 39, 79 mos of TP/AP), 5 to Remicade (after 3, 3, 17, 19, 27 mos of TP/AP) and 1 required surgery 2 mos after starting TP/AP. No child discontinued therapy due to hepatotoxicity. Therapy was briefly held in 3 due to leucopenia, but ANC remained >1500 and/or WBC >5. No serious infections occurred. One patient was diagnosed with a pseudopapillary pancreatic tumor 1 mos after TP/AP and underwent a Whipple procedure within 5 mos.
Conclusion: TP/AP was well tolerated up to a maximum follow-up of 85 mos, and effectively rescued 50% of children who had previously not responded to thiopurine monotherapy. TP/AP may be a safe and effective option for children whose families are hesitant to initiate alternative immunomodulatory or biologic therapy.
236 CONCOMITANT USE OF METHOTREXATE RESULTS IN HIGHER 14-WEEK INFLIXIMAB TROUGH LEVELS IN CHILDREN WITH INFLAMMATORY BOWEL DISEASE
Lesley Small, Robbyn Sockolow, Kimberley Chien, New York Presbyterian Hospital Weill Cornell Medicine, New York, NY, USA
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder that often has an unpredictable clinical course. Methotrexate and Infliximab (IFX) are effective therapies for IBD and can be used individually as monotherapy or in combination (concomitant therapy.) The goal of this study was to compare pediatric patients with IBD on IFX monotherapy to patients on concomitant therapy with IFX and Methotrexate specifically with regard to 14-week IFX trough and antibody to infliximab (ATI) levels. The secondary objective was to compare the groups with regards to change in the pediatric Crohn's disease activity index score (PCDAI), mean corpuscular volume (MCV) and C-reactive protein (CRP) over the first 14 weeks of therapy. The study's aim was to show that concomitant therapy with IFX and Methotrexate resulted in higher IFX trough levels and prevented the development of immunogenicity with antidrug antibodies.
This was a retrospective chart review of all patients with a diagnosis of Crohn's disease, ulcerative colitis and IBD-unspecified who received IFX between 2010 and 2015 at a single tertiary care center. Inclusion criteria were patients previously naïve to biologic therapy who were started on IFX and had IFX trough and ATI levels checked at 14 weeks of therapy. The excluded patients were those started on methotrexate after starting IFX, patients on a thiopurine or patients who did not follow standard IFX induction dosing. Included patients were divided into two groups: those on monotherapy with IFX and those on concomitant therapy. Both groups had week 14 IFX trough and ATI levels assessed and also were evaluated for change in PCDAI score, CRP and MCV from week 0 to week 14 of therapy.
32 patients met inclusion criteria: 10 patients on concomitant therapy and 22 patients on monotherapy. Demographics including disease scores at the start of therapy were similar between the two groups with the exception of sex; 100% of the patients in the monotherapy group were male while only 45% of patients in the concomitant therapy group were male. IFX trough levels at week 14 of therapy were significantly higher in the concomitant therapy group as compared to the monotherapy group (10.3 +/- 5.6 versus 5.9 +/- 3.7 p
= 0.0119). There was a trend towards significance when ATI levels were grouped as positive or negative (10 vs. 36% p
= 0.12) but overall the difference still lacked significance. There was no significant difference in the change in PCDAI score, CRP or MCV from week 0 to week 14 when the groups were compared.
This is the first pediatric study examining the effects of concomitant IFX therapy with methotrexate on 14-week IFX trough and antibody to IFX levels compared to IFX monotherapy alone. This study shows that the use of concomitant methotrexate promoted higher IFX trough levels after the completion of induction dosing. There was no significant difference in ATI levels between the two groups which may be secondary to small sample size.
237 POSTOPERATIVE COMPLICATIONS IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE TREATED WITH VEDOLIZUMAB
Lori Zimmerman, Jill Zalieckas, Robert Shamberger, Athos Bousvaros, Boston Children's Hospital, Boston, MA, USA
Background: Vedolizumab is a gut-specific α4β7 integrin inhibitor with efficacy in Ulcerative Colitis (UC) and Crohn's disease (CD). Vedolizumab affects leukocyte adhesion in the gut, a process important for wound healing, thus raising concern for postoperative complications in patients treated with vedolizumab prior to surgery. As there is minimal data on postoperative complication risk in patients treated with vedolizumab, the aim of this study was to examine the rate of postoperative complications in a cohort of patients treated with vedolizumab who required surgery at our institution.
Methods: By surveying the electronic medical record, we identified a cohort of patients with CD or UC who were treated with vedolizumab at Boston Children's Hospital from 2014–2016 and were followed for at least 3 months. Data on demographics, operations, concurrent medications, disease phenotype, and response to vedolizumab was extracted from the record. The specific postoperative complications were described.
Results: At our institution, 31 patients (mean age 17.2 years ± 3.7 years SD, range 9–24 years) with CD (n = 21) and UC (n = 10) have been treated with vedolizumab for refractory disease. 30/31 patients had failed 1 TNF α inhibitor and 21/31 had failed at least 2 TNF inhibitors prior to vedolizumab administration. 13/31 patients required surgery following initiation of vedolizumab. The operations included diverting ileostomy (n 6), laparoscopic proctocolectomy with ileoanal J-pouch and diverting ileostomy (n = 6), and ileocecal resection (n = 1). 8/13 (61%) patients had a postoperative complication, including 5 complications associated with poor wound healing or infection (intra-abdominal abscess [n = 1], mucocutaneous separation at the ileostomy [n = 3], stoma-related small bowel obstruction requiring ostomy takedown [n = 1]) and 3 other complications (seizure [n = 1] and readmission for pain and dehydration [n = 2]).
Conclusion: Patients who receive vedolizumab often have refractory disease and are likely to require surgery. This study highlights the high postoperative complication rate in patients treated with vedolizumab who require surgery at our institution. Large multicenter studies are required to further examine the risk of postoperative complications in patients treated with vedolizumab.
238 INCIDENCE OF DENTAL CARIES AMONG A PEDIATRIC POPULATION DIAGNOSED WITH INFLAMMATORY BOWEL DISEASE
Mafalda Ramos1, Henedina Antunes2, Irene Pina Vaz1,1University of Porto, Porto, Portugal,2Hospital de Braga; Institute of Life and Health Sciences (ICVS); Health Sciences School of the University of Minho and Associated Laboratory ICVS / 3B's, Braga/Guimarães, Po, Braga, Portugal
Introduction: Inflammatory Bowel Disease(IBD) can manifest itself in the oral cavity. The DMDF measures the average number of Decayed, Missing and Filled teeth and the World Health Organization (WHO) set 1.50 as the target to 2020, in Portugal.
Aim: To characterize the state of oral health in patients diagnosed with Inflammatory Bowel Disease(IBD) at pediatric age and compare it with a same-age healthy sample at a school in the same district.
Methods: Observational descriptive study,with survey application and direct evaluation of the oral cavity, based on the DMFD index of patients diagnosed with IBD at pediatric age (cases) from a tertiary hospital. The control group was healthy children and adolescents from a school. The oral cavity was photographed. The statistical analysis used the Chi-square test.
Results: From a database of 72 patients with IBD at pediatric age, 55 phone calls were answered: 5 people weren’t in the country and 50 agreed to an appointment at the hospital to participate in the study. One IBD patient missed the appointment and 49 IBD patients completed the protocol: 34 affected by Crohn's disease,14 cases of ulcerative colitis (UC) and 1 indeterminate case. Inthe control group, the authors sent the parents of 50 children and adolescents a written consent and 26 completed the protocol. The DMFD average, in the IBD sample, was 3.22 versus 5.19 in the control group, p
= 0.036. The IBD patients had a mean age ± standard deviation of 17.49- ± -4.94 years and the control group average age ± standard deviation was 17.42 ± 0.50 years, p
= 0.981. Regarding the number of cavities present at the time of evaluation; the case group had an average of 2.37, and the control group 2.92, p
= 0.340. In Crohn's disease, the DMFD was 3.35, while the UC value was 2.86, p
= 0.627. The recurring presence of ulcers in IBD group occurred in 20.4% people. 75.52% subjects in the IBD group used immunosuppressants; UC patients didn’t use them. The DMFD average proved to be higher when the diagnosis preceded 7 years of age (permanent teeth age formation) in the IBD group. The number of brushings, meals and cleanings weren’t negligent in the patient population. 46.9% of patients only see the dentist when feeling pain. In the control population, there was also a good level of care and dental hygiene, with longer gaps between trips to the dentist than that observed in the patient population. Sweetened foods were regularly consumed by 79.5% of IBD patients, while in healthy population it occurred in 50% of individuals.
Conclusions: The prevalence of decayed teeth in the IBD group, according to the DMDF index, was significantly lower than the healthy sample one, even if the control population healthcare was better and candy consumption in the diseased population was higher. There were no significant differences between the types of IBD and cariogenic index of the individual. The IBD diagnosis before 7 years old may be important to prevent tooth decay, perhaps for the special care of young children with IBD.
239 DIFFERENTIATION OF CROHN'S DISEASE AND ULCERATIVE COLITIS IN CHILDREN BASED ON THE SERUM CYTOKINE PROFILE
Maiko Tatsuki1, Reiko Hatori1, Akira Aizawa1, Ishige Takashi1, Seiichi Kagimoto2, Takeshi Tomomasa3, Hirokazu Arakawa1,1Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan,2Saitama Children'sMedical Center, Saitama, Japan,3Pal Children's Clinic, Japan,
Background and Aims: Cytokines have been directly implicated in the pathogenesis of inflammatory bowel diseases (IBDs) such as Crohn's disease (CD) and ulcerative colitis (UC). In recent genetic and immunological studies, they appear to play a crucial role in controlling intestinal inflammation and the associated clinical symptoms of IBD. However, the changing cytokine production patterns in pediatric IBDs has not yet been well established. The aim of this study was to investigate the expression of the cytokine profile in pediatric IBDs and to differentiate between CD and UC based on the serum cytokine profile.
Methods: Seventy-three children (48 boys and 25 girls) aged from 5.8 to 17.3 years were enrolled in this study. This group included 20 patients with CD (CD group), 20 with UC (UC group), and 33 with non-IBDs (control group). Diagnosis of CD and UC was based on case histories and clinical, laboratory, endoscopic, and histological data. The control group included healthy subjects as well as patients with functional constipation and irritable bowel syndrome. Disease activity in patients with IBDs was assessed using the Pediatric CD Activity Index (PCDAI) or the Pediatric UC Activity Index (PUCAI).
A total of 27 cytokines, chemokines, and growth factors (IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, Eotaxin, FGF-basic, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1ɑ, MIP-1β, PDGF, RANTES, TNF-ɑ, and VEGF) were determined in the blood sera using a double-beam laser automatic analyzer (BioPlex Protein Assay System; BioRad, USA).
Results: Cytokine distribution in the sera is presented in Table 1. Three cytokines (IL-1β, PDGF, and RANTES) were excluded as levels were out of range. The levels of IL-6, and G-CSF were significantly increased in the CD and UC groups when compared with those in the control group. Furthermore, the levels of IL-15, MCP-1, and MIP-1ɑ were significantly increased in the CD group when compared with the UC group. Multivariate logistic regression analysis revealed that three cytokines, MCP-1, TNF-ɑ, and Eotaxin as good biomarker potential for differentiating between CD and UC using the serum cytokine profile.
Conclusion: There is potential for differentiation between patients with CD and UC using serological methods for adaptable cytokine measurement.
240 CHARACTERIZATION OF THE INTESTINAL MICROBIOME OF VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE
Maire Conrad1, Noor Dawany1, Kyle Bittinger1, Robert Baldassano1, David Piccoli1, Frederic Bushman2, Marcella Devoto1, Judith Kelsen1,1Children's Hospital of Philadelphia, Philadelphia, PA, USA,2University of Pennsylvania School of Medicine, Philadelphia, PA, USA,
Inflammatory bowel disease (IBD) is a multigenic and environmentally triggered disease resulting in a dysregulated immune response to commensal or pathogenic microbes in the intestinal tract. Very early onset (VEO-IBD), IBD diagnosed <5 years of age, can present with a more aggressive phenotype and there appears to be a more prominent genetic contribution to the disease compared to older patients. However, the rapidly increasing incidence and prevalence of VEO-IBD points to an environmental and gut microbiome influence in disease development as well. Using shotgun metagenomic sequencing, we previously analyzed the gut microbiome of a prospective pediatric Crohn's disease cohort initiating therapy.1 Here, we aim to characterize the intestinal microbiome of patients with VEO-IBD who have had whole exome sequencing (WES) performed, and to compare the results to the previously analyzed cohort of older pediatric patients with IBD. Stool samples were collected from subjects diagnosed with VEO-IBD who underwent WES. Genomic DNA was prepared from whole stool and sequenced using the Illumina HiSeq paired-end method. Reads were aligned to the human genome to identify human DNA in the sequencing results. Taxonomy was assigned using MetaPhlAn2 and confirmed by One CodeX, which identifies clade-specific marker genes from bacterial, fungal, archaeal, and viral sources. Samples were compared to post-therapy samples from older-onset IBD patients. Among the samples obtained, 35 stool samples from VEO-IBD patients were analyzed and were compared to 80 older-onset IBD patients and 24 healthy controls from prior studies.1,2 Samples were compared by the percentage of shared species (Jaccard distance), and clustering was performed by the method of partitioning around medoids. Two clusters were detected in the combined dataset. One cluster was near to healthy controls (Figure 1, cluster 1). The second cluster was more distant from the healthy controls, and had lower diversity and altered bacterial composition (Figure 1, cluster 2). The VEO-IBD patients in cluster 2 were diagnosed in the first 3 years of life and had increased disease severity as compared to cluster 1. This distinction was seen in older-onset IBD as well. In addition, percentage of human DNA detected in the stool sample was greater in cluster 2, similar to the older-onset IBD cohort.
Two clusters were detected in the microbiome composition of patients with VEO-IBD, reflecting our previous findings in older-onset IBD. The two clusters were associated with clinical features of disease severity. Further studies are ongoing to include a larger cohort of VEO-IBD. In addition, analyses are being performed to associate the microbiome composition with host genomic data and clinical characteristics in the VEO-IBD cohort.
1. Lewis JD et al. Cell Host Microbe 2015;18(4):489–500; 2. Wu GD et al. Science. 2011;334(6052):105–8.
Table: Dysbiotic Cluster in Pediatric IBD
241 THERAPEUTIC DRUG MONITORING IS A NEW TOOL FOR IMPROVING THE CARE OF PATIENTS TREATED WITH ANTI-TNF ALPHA: DOES THIS APPLY TO CHILDREN WITH INFLAMMATORY BOWEL DISEASE?
Mallory Chavannes1, Prevost Jantchou1, France Gervais1, Robert Robitaille2, Valérie Marchand1, Colette Deslandres1,1CHU Sainte Justine, Montreal, QC, Canada,2Hôpital Maisonneuve Rosemont, Montreal, QC, Canada
Introduction: Infliximab (IFX) was proven effective in the induction and maintenance of remission in IBD in both children and adults. However, there is a significant number of individual who lose clinical response to the medication. Monitoring of serum IFX drug level was shown to correlate with clinical response, and mucosal healing. Few studies demonstrate similar benefits in children, some suggesting that perhaps the target serum level of antiTNF in children should be higher than in adults.
Objective: To review our experience with therapeutic drug monitoring (TDM) in children with inflammatory bowel disease (IBD) treated with IFX. The primary objective was to assess the serum levels of IFX in children aged 5–18 years during the maintenance period. The secondary objectives were to correlate the levels with clinical response and to assess the proportion of patients in which a proactive dose adjustment approach had been taken.
Methods: This was a single-center retrospective cohort study. Patients were included if they had at least one serum level of IFX between June 2014 and November 2015, and had a follow-up of at least 3 months after the levels were drawn. We collected all trough levels drawn during maintenance phase. All levels were analyzed using the progenika promotor-IFX ELISA technique. We collected biochemical markers drawn a maximum of two weeks prior to the IFX level. We also collected clinical assessments at the time of IFX infusion as reported by the patient. This outcome was graded on a three-point scale (well, moderately well and unwell). The physician global assessment was also recorded if it was done within 4 weeks of the IFX level.
Results: During the study period a total of 301 children were receiving IFX. Among them, 188 children had at least one IFX serum level. From the first 102 patients (59.8% boys; 232 IFX levels) evaluated we excluded the 45 serum levels drawn during induction. IFX was started with a mean interval of 19 weeks from diagnosis (Range 0–130.6 weeks) at a dose of 5 to 10 mg/Kg/dose depending on disease severity. Twenty seven percent were on combination therapy with the majority on methotrexate (65.3%). The 84 patients in maintenance phase had a total of 187 serum IFX levels drawn. The median trough IFX level was 6.6 ug/mL for children with UC and 3.61 for children with CD (Range 0.01–14.4) taken at a median dose interval of 7 weeks. Serum IFX levels were comparable between males and females. Levels were subtherapeutic in 43% and supratherapeutic in 33%. Clinical status as reported by patients did not correlate with IFX levels.
Conclusion: Despite dose adjustments, nearly 50% of serum IFX levels were sub-therapeutic, although the majority of the patients reported feeling well. TDM of IFX is therefore mandatory in the treatment of IBD and patient self-reported clinical status is not an indicator of adequate levels.
242 CLINICAL OUTCOMES IN PAEDIATRIC ULCERATIVE COLITIS: A SINGLE-CENTRE COHORT STUDY.
Marco Gasparetto, Vivien Wong-Spracklen, Franco Torrente, Robert Heuschkel, Mary Brennan, Gabriele Noble-Jamieson, Matthias Zilbauer, Cambridge University Hospitals, Addenbrooke's, Cambridge, Cambridgeshire, UK
Objectives and study: The disease course of children with ulcerative colitis (UC) can vary substantially, and published data on clinical outcomes remains scarce. We describe the outcomes of children and adolescents with UC or unclassified inflammatory colitis (IBD-U) based on induction treatment and requirement for subsequent medical and surgical treatment interventions focusing on the first 18 months upon diagnosis.
Methods: We retrospectively identified all patients aged 2 to 18 years diagnosed with UC or IBD-U in our centre between September 2006 and February 2014, with a minimum follow-up of 18 months. For all patients we recorded the type of induction treatment (i.e., steroids or 5-Aminosalicylic acid (5-ASA)) received within 3 months from diagnosis; maintenance therapy at 6, 12 and 18 months follow-up; commencement dates of second-line therapy such as Azathioprine (AZA), 6-mercaptopurine (6MP); and requirement for third-line therapy (i.e., biologics) and surgical intervention (i.e. colectomy). Patients were stratified into 3 different groups based on their requirements for escalation therapy over an 18-month period: mild disease course maintained on 5-ASA alone (Group 1); moderately severe disease course requiring escalation to AZA or 6-MP (Group 2) and severe disease course requiring biologics (IFX) and/or colectomy (Group 3).
Results: 93 patients were included in our study with a mean follow-up duration of 59.2 months +/- SD 33.4 months (median 49.7 months, range 18–195 months). 58/93 (62.3%) were diagnosed with UC and 35/93 (37.6%) with IBDU colitis. The mean age at diagnosis was 11.7 years (+/- SD 3.12 years, range 2.2 - 17 years). 77/93 (82.8%) required induction of remission with steroid therapy, while only 16 patients (17.2%) were started on 5-ASA as induction treatment upon diagnosis. During 18 months follow-up, 38/93 (40.9%) patients were stratified into Group 1, 38/93 (40.9%) into Group 2, and 17 patients (18.2%) into Group 3. Within Group 3, 15/17 (88.2%) patients progressed to IFX therapy, out of which 12/15 (80%) required IFX as part of their treatment for acute severe colitis (ASC) (80%) and 3/15 (20%) received IFX as maintenance treatment for chronic active colitis (CAC). 6/12 (50%) patients experiencing ASC were found to progress from IFX to colectomy.
Conclusion: Our study provides important insight into disease behaviour and outcome in children diagnosed with UC and UC-like IBDU. The data indicates that only a relatively small proportion (18%) of patients with UC and IBDU- colitis experience an aggressive phenotype, characterised by a rapid progression to treatment with IFX and/ or requirement for colectomy within 18 months from diagnosis. Importantly, in our cohort, 50% of patients receiving IFX for ASC failed to respond to medical therapy and required colectomy. Future work has to focus on identifying reliable disease prognostic biomarkers, which allow early detection of at risk patients and preventative treatments.
243 CREATING A PROCESS TO OBTAIN HEPATITIS B SEROLOGY AMONG PATIENTS TREATED WITH INFLIXIMAB AT A LARGE URBAN CHILDREN'S HOSPITAL
Marie Raphaelle Jean, Ann Weaver, Teresa Mastin-Diebold, Krista Kissinger, Emily Smitherman, Leslie Favier, Lara Danziger-Isakov, Rebecca Brady, Jennifer Huggins, Shehzad Saeed, Pam Morgan, Dana MH Dykes, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
Background: Hepatitis B infection is a significant public health challenge despite improvements in vaccination efforts, especially in the setting of today's heroin epidemic. A particularly vulnerable population includes patients treated with chronic immunosuppressive therapy, including patients on infliximab for inflammatory bowel disease (IBD) or rheumatic disease. The risk of reactivation of hepatitis B while on immunosuppressive therapy is considerable with reports of up to a 25% mortality rate. Patients on these medications should be screened with hepatitis B surface antibodies (anti-HBs) for evidence of immunity in addition to hepatitis B surface antigen (HBsAg) and hepatitis B core antibodies (anti-HBc) for evidence of acute or chronic infection. Our aim was to develop a process to reliably complete hepatitis B screenings on patients receiving infliximab within the gastroenterology (GI) and rheumatology divisions at Cincinnati Children's Hospital and Medical Center (CCHMC).
Methods: Providers from GI and rheumatology at CCHMC recognized common barriers to obtaining hepatitis B serology. Eligible patients included all GI and rheumatology patients receiving infliximab between October 2015 and March 2016. Using quality improvement methodology and the “Plan-Do-Study-Act” (PDSA) approach, several interventions were designed which centered around: education of clinic providers and nurses, pre-visit planning resulting in ordering of serology, and the development of physician “talking points” for patients.
Results: While 48% of the IBD patient population had previously been screened for anti-HBs, no patients from either division had a complete set of hepatitis B serology prior to the intervention. A total of seven PDSA cycles were performed during the 32-week intervention period (see Figure 1) which resulted in an increase in patients screened from 0% to 85%. By March 2016, a total of 270 patients (220 GI, 50 rheumatology) had up-to-date hepatitis B serology. Appropriate ordering of the hepatitis B serology and “talking points” for the provider had the greatest impact on successful screening.
Conclusion: We were able to develop a method to obtain hepatitis B serology on at-risk patients on infliximab within two subspecialty divisions within a large children's hospital. Next steps will be to develop a process to reliably provide vaccines for patients who are seronegative, expand this process to all patients who are identified as immunocompromised within GI and rheumatology, and then expand this process to other divisions at CCHMC.
244 IS THERE A CORRELATION BETWEEN ANTI-TUMOR NECROSIS FACTOR TROUGH LEVELS AND THE OCCURRENCE OF PARADOXICAL CUTANEOUS AND ARTICULAR MANIFESTATIONS IN CHILDREN WITH INFLAMMATORY BOWEL DISEASE (IBD)?
Frank Ruemmele, Benedicte Pigneur, Hôpital Necker-Enfants Malades, Paris, France
Background: Anti-tumour necrosis factor (TNF) agents have dramatically improved the prognosis of IBD and are widely used in adult and pediatric IBD patients. However, despite their good safety profile, use of these agents may lead to paradoxical manifestations involving skin or joints. Pathogenesis of such side effects is poorly understood and may involve anti-TNF pharmacokinetics.
Objective: The aim of our study was to look for an association between the use of anti-TNF agents trough levels and the occurrence of adverse events like skin reactions or joint pain.
Materials and Method: Pediatric IBD patients treated with anti TNF agent (Infliximab or adalimumab) for maintenance therapy were included in a cross-sectional prospective monocentric study. At inclusion, patients had a dosage of anti-TNF trough levels and/or antibodies measurement and were assessed for paradoxical manifestations: skin manifestations, joint pain, fatigue. Clinical remission was assessed with the PUCAI and PCDAI score for UC and CD. Skin problems as rash, xerosis and pruritus were evaluated during the clinical examination. Side effects such as fatigue and arthralgia were measured with a visual analogic score (VAS).
Results: 117 pediatric patients with a diagnosis of IBD (102 with Crohn's disease and 17 with ulcerative colitis) were included in the study. Skin manifestations (such as eczema, cheilites, acne) were observed in 55/117 patients (47%). Eczema was the most commonly described skin manifestation (n = 37, 31%), followed by acne (n = 12; 10%) and folliculitis (n = 8; 6%). The strongest association factor for skin manifestations was Crohn's disease, in nearly 85% of afflicted patients. In addition, 7/117 (0.05%) of patients developed arthritis during anti-TNF alpha treatment. Any correlation was found between TNF trough level and the appearance of skins and joint manifestations (p
= 0.01, p
= 0.1, respectively).
Conclusions: Anti-TNF alfa therapy is frequently associated with newly onset skin reactions, most commonly in patient affected by Crohn's disease. However,no correlation was found between high TNF trough level and the occurance of dermatological and articular manifestations.
245 IMMUNIZATION RATES FOR PPSV23 (PNEUMOVAX) IN IMMUNOCOMPROMIZED PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASE: ROOM FOR IMPROVEMENT
Mary Ayers, Lori Mahajan, Anthony Anani, Elizabeth Collyer, Cleveland Clinic Childrens, Cleveland, OH, USA
Background: Protection against vaccine preventable diseases in immunocompromised patients is important as these patients have impaired host defenses. These patients also have greater exposure to pathogens due to frequent contact with medical environments which leads to an overall increased risk or severity of vaccine-preventable infection. However, vaccination rates are frequently suboptimal as clinicians have insufficient or inaccurate information concerning recommended immunization schedules of such patients. Specialty clinicians may also lack the infrastructure needed to administer vaccines to their at-risk patient populations. PPSV23 has been shown to decrease severe pneumococcal infections. Advisory Committee on Immunization Practices (ACIP) recommends it for children greater than or equal to 2yrs of age with chronic inflammatory illnesses prior to starting or while on immunosuppressive therapy.
Objective(s): 1) determine rate of immunization for PPSV23 in our IBD patients receiving immunosuppressive therapy with Infliximab (IFX) in the Cleveland Clinic Pediatric Gastroenterology (GI) department; 2) if rate determined to be suboptimal, increase rate of immunization for PPSV23 by >10% in this patient population.
Methods: A quality improvement project was devised to sequentially review the charts of patients that received IFX over a 2 month period to assess baseline PPSV23 Immunization rates. ACIP recommendations for PPSV23 immunization in immunocompromised patients were subsequently presented at pediatric GI grand rounds in addition to chart review results. Immunization rates were then determined at 2 months and 8 months following the educational intervention in the cohort of pediatric GI patients with IBD receiving IFX.
Results: Table 1.
PPSV23 counseling and immunization rates in pediatric patients receiving IFX vs. Influenza vaccination rates
Conclusions: 1) Suboptimal immunization rates for PPSV23 were identified in pediatric IBD patients receiving IFX. 2) Single educational intervention resulted in an increase in PPSV23 immunization rates from 7.0% at baseline to 16.7% at 8 months. While it is difficult to comprehensively address all patient needs in this complex sub-set of pediatric patients, it is important for pediatric subspecialists to be aware of the ACIP recommendations on immunization of immunocompromised patients and work to improve the immunization rates. In our institution, a sustained effort with multiple iterations of the PDSA cycle to get the immunization rates for PPSV23 at par with the immunization rates for Influenza is planned.
246 ACTIVE LOCALIZED ILEO-CECAL CROHN'S DISEASE IS ASSOCIATED WITH EARLY STRICTURING AND POOR MEDICAL OUTCOMES IN CHILDREN.
Massimo Martinelli, Annamaria Staiano, Caterina Strisciuglio, Francesca Paola Giugliano, Marialuisa Andreozzi, Erasmo Miele, University of Naples, Naples, Italy
Background: Localized ileo-cecal (IC) disease is a specific CD phenotype whose prevalence and natural history in pediatric age is not well characterized. The aims of this study were to evaluate and compare the natural history and the outcomes of medical therapy in IC CD children at diagnosis with pediatric patients showing different CD localizations.
Methods: We reviewed charts of children diagnosed with CD at our referral center from January 2005 to December 2014. Only patients with luminal CD and with a minimum follow-up of 6 months were included in the study. Demographic characteristics, disease localization, behaviour at diagnosis and during the follow-up, induction therapy and need for treatment escalation, including immunosuppressants (IM), biologics, endoscopic/surgical therapies, were collected. Patients were then divided into Group 1 (IC CD children) and Group 2 (remaining luminal CD patients).
Results: Seventy- four CD children were identified, of whom 23 (31%) had a localized IC CD (median age: 17 yrs) and 51 (69%) had other luminal localizations (median age: 15.9 yrs). Among the 51 children of group 2 CD localization was: L1 (n = 11, 21.6%), L2 (n = 10, 19.6%), L3 (n = 28, 54.9%) and L4 (n = 11, 19.6%). Median follow-up was 49.5 months (range: 6–154). Median age at diagnosis was not significantly different between the two groups (12.8 yrs vs. 10.5 yrs; p
= 0.1), as well as induction therapy (p 0.1). Eight out of 23 children of group 1 presented with stricturing behaviour at diagnosis versus none of Group 2 (p < 0.001); 16 out of 23 patients (69.5%) developed a stricture during disease course versus 3/51 (5.8%) of group 2 (p < 0.001). Twenty out of 23 (87%) patients with IC CD started an IM [Azathioprine (AZA):17 (85%); methotrexate (MTX): 3 (15%)] versus 21 out of 51 children of Group 2 [(AZA: 19 (90.4%); MTX: 2 (9.6%)] (p < 0.001). A higher number of patients of Group 1 needed to switch to another IM when compared with Group 2 [10/20 (50%) vs. 4/21 (19%); p
= 0.05]. More children with IC disease started biologics with a trend towards statistical significance [7/23 (30.4%) vs. 7/51 (13.7%); p
= 0.08)]. Nine out of 23 (39.1%) children of Group 1 underwent surgery or endoscopic dilation compared with 2 out 51 (3.9%) patients of group 2 (p < 0.001). Seven out of 9 patients (77.7%) of group 1 had a sustained remission after surgical procedure with a median follow-up of 28 months (range 7–42 months).
Conclusion: Patients with localized IC CD show a more severe disease, including early stricturing and need for therapy escalation. Our data suggest that IC CD should receive a top-down strategy and that early elective surgery as a first line treatment should be evaluated in future studies.
247 MONITORING AND TREATMENT OF VITAMIN D LEVELS IN CHILDREN WITH INFLAMMATORY BOWEL DISEASE.
Kiki Fockens, Matthew Egberg, Sean Murphy, Paul Rufo, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA
Background and Aims: Vitamin D is an essential micronutrient in regulating calcium absorption and overall bone mineralization. Recent studies have also demonstrated that vitamin D plays a role in the maturation and maintenance of normal immune function. Patients with inflammatory bowel disease (IBD), often struggle to maintain micronutrient sufficiency. Assessment of vitamin D status in children with IBD is an area of active interest due to growing data demonstrating the potential role played by vitamin D in immune homeostasis. However, physician practice remains highly variable with respect to identification and treatment of patients with vitamin D deficiency. The aim of this study is to identify variation in the monitoring and treatment of vitamin D status in pediatric patients with IBD at a single tertiary care center.
Methods: We conducted a retrospective chart review of all pediatric IBD patients with 25-OH vitamin D levels drawn between January 2014 and December 2014. Vitamin D deficiency was defined as a serum 25-OH vitamin D level less than 32 ng/mL. Initial and follow-up Vitamin D levels were recorded. Concurrent serologic labs, as well as the presence or absences of Vitamin D supplementation was also collected. Data was collected from patients enrolled and not enrolled in the Improved Care Now network.
Results: We identified a total of 500 patients for inclusion in the study; 65.6% were enrolled in the Improved Care Now (ICN) network. 63.6% of IBD patients were deficient in vitamin D with a mean level of 23.8 ng/mL (SD 5.9). There was no difference in the prevalence of vitamin D deficiency rates between those patients enrolled in ICN and those not enrolled; nor was there a difference in rates of subsequent supplementation (in vitamin D deficient patients) between the two groups. Initial vitamin D levels were checked most frequently in January. In those with vitamin D levels less than 32 ng/mL, 61.6% were not prescribed supplementation. In those who were prescribed supplementation, 14.5% received 50,000 IU weekly for an average of 7 weeks. The mean change in vitamin D levels for those supplemented with 50,000 IU weekly was 13.9 ng/mL (SD 10.9) as compared to a mean change of 5.5 ng/mL (SD 7.6) in patients supplemented with lower doses (p < 0.0001). Mean duration between vitamin D levels was 215 days (SD 153). Supplementation with high dose (50,000 units) vitamin D was a significant explanatory variable with respect to variation in change to vitamin D levels even after controlling for gender, ethnicity, CRP, and BMI.
Conclusion: Vitamin D deficiency is highly prevalent in the pediatric IBD population. Treatment rates for Vitamin D deficiency are poor despite good responses in those treated with high dose supplements.
248 ENTERIC VIROME AND BACTERIAL COMMUNITY IN CHILDREN WITH ULCERATIVE COLITIS AND CRONH DISEASE
Melissa Fernandes1, Melvin B Heyman1, Phan Tung1, Emily Stekol1, Brandon Lamere1, Susan V. Lynch1, Katherine Elise Jamboretz2, Eric Delwart1,1University of California – San Francisco, CA, USA,2University of San Francisco, San Francisco, CA, USA
Purpose: Pediatric inflammatory bowel disease (IBD) is believed to be caused by a combination of genetic, environmental, and autoimmune factors. Recent evidence supports contribution of the enteric microbiome. Intestinal dysbiosis has been reported in children with IBD. We examined the enteric virome and bacterial community composition of children with Crohn disease (CD) or ulcerative colitis (UC) to test the hypothesis that unique patterns of viral organisms and/or presence of bacterial pathogens contribute to the pathogenesis of IBD in these patients.
Methods: Fecal samples from children diagnosed with CD or UC and similar aged children with no known intestinal disease were processed to determine individual viromes. In the six weeks prior to collection, 2 IBD patients had self-reported non-infectious diarrhea, all other patients denied diarrheal symptoms. Five (3 IBD, 2 control) patients were on prebiotics at time of sample collection; no IBD patients received antibiotics during the four weeks prior to collection, one control received antibiotics five days prior to collection. Classification of IBD disease extent varied: CD: 4 ileocolonic, 1 ileal, 2 colonic; UC: 2 right colon, 3 pancolitis. Following collection, for virome analysis fecal suspensions were centrifuged, filtered and treated with a mixture of DNase and RNase enzymes. Viral sequences were identified through translated protein sequence similarity search (BLASTx) to annotated viral proteins available in GenBank's databases. The twenty most common phages in each sample were selected and the number of sequence reads compared in CD, UC and healthy controls. DNA was extracted from fecal samples using cetyltrimethylammonium bromide, prior to amplification and sequencing of the V4 region of the 16S rRNA gene. Quality filtering, chimera-checking and data analyses were performed in QiiME. IRB approval was obtained prior to initiation of this study.
Results: Samples were obtained from 24 children (7 CD, 5 UC; 12 control). Mean age was 12.2 years; 54% were male, and mean BMI was 19.4. Virome analyses focused on bacterial viruses. No differences were found in phage content between the groups (UC, Crohn's, and control). Bacterial community analysis is ongoing and will be related to patient health status.
Conclusions: Increasing focus has been placed on the enteric biome in IBD. While other investigators have identified unique viral patterns in adults with IBD, our study does not support prior studies and is unable to replicate this finding in pediatric patients. This study is limited by a small sample size and heterogeneity among IBD patients in terms of treatment and disease severity and location.
∗249 FECAL CALPROTECTIN IS A VALUABLE SCREENING TOOL IN A LARGE NORTH AMERICAN PEDIATRIC GASTROENTEROLOGY CENTER
Michael K. Wang, Priya Raj, Richard Kellermayer, Texas Children's Hospital/Baylor College of Medicine, Houston, TX, USA
Background: Fecal calprotectin (FC) is a valuable non-invasive screening tool for the detection of lower gastrointestinal (GI) pathology, including inflammatory bowel disease (IBD). Most studies (especially in children) in this respect originate from Europe with potentially differing medical practice from the United States (US).
Objectives: To determine the negative predictive value of FC for lower GI pathology within a large pediatric gastroenterology center of the US.
Methods: This retrospective study was conducted at Texas Children's Hospital, assessing colonoscopies between January 2009 and December 2015, where a FC was obtained within 1 month of that colonoscopy. Only cases without established GI diagnoses (i.e. diagnostic endoscopy) prior to the index colonoscopy were selected. C-reactive protein (CRP), rectal bleed (both self-reported and fecal occult blood results), indication for colonoscopy, colonoscopy findings (macroscopic and microscopic), treatment change within a month after colonoscopy, and final diagnoses were recorded. Three laboratories performed the FC test. Normal values by laboratories were: ≤50 μg/g (ARUP Laboratories, Salt Lake City, UT), ≤120 μg/g (LabCorp, Burlington, NC), and ≤162.9 μg/g (Quest Diagnostics, San Juan Capistrano, CA). We also examined a combination of FC with both CRP and rectal bleed (triple screen).
Results: 194 out of 3742 colonoscopies (5.2%) met inclusion criteria. Of those, 115 patients (59.3%) had normal colonoscopies. Of the 69 patients diagnosed with a lower GI disease, 47 (24.2% of total) were diagnosed with IBD. When using lab-specific reference ranges for FC, 84 (43.3%) cases had a normal FC (median 42.3 μg/g). Lab-specific reference FC screening would have missed 10 out of 79 (12.6%) abnormal colonoscopies and 3 of the 47 (6.4%) IBD cases. Using a FC cutoff of 50 μg/g would have missed none of the IBD cases, and only 4 of 79 (5.1%) of abnormal colonoscopies. The triple screen (all negative: lab-specific FC, CRP, rectal bleed) would have missed none of the IBD cases and only 2 (2.7%) of the abnormal colonoscopies, which had final diagnoses of pinworms and eosinophilic esophagitis. Therefore, none of the triple screen negative cases would have required a colonoscopy to establish the conclusive GI diagnosis. Table 1 summarizes the predictive values of the screens utilized in our study.
Conclusions: This work confirms the outstanding negative predictive value of FC as a screening tool for lower GI pathology, especially IBD in a US-based tertiary care pediatric practice. Combination of FC with CRP and rectal bleeding can further its clinical utility. This triple screening method could have prevented 48.9% (45 of 92) of normal colonoscopies within our cohort. We propose that the judicious use of FC may help avoid a large number of unnecessary colonoscopies in children.
250 CLINICAL MANIFESTATIONS OF THIOPURINE S-METHYLTRANSFERASE VARIANTS IN KOREAN PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASE
Mijin Kim, Ilsan Paik Hospital, Inje University College of Medicine, Goyang-si, Gyeonggi-do, South Korea
Background: Azathioprine (AZA) is used to maintain clinical remission in inflammatory bowel disease (IBD). Thiopurine S-methyltransferase (TPMT) is the key enzyme in the metabolic pathway of thiopurine compounds and its activity is largely influenced by polymorphisms of the TPMT gene. This study evaluated the clinical manifestations of TPMT variants in Korean pediatric IBD patients.
Methods: A total of 293 IBD patients who required AZA to maintain remission were genotyped for TPMT. There were 209 Crohn's disease patients and 84 ulcerative colitis patients ranging in age from 3 to 21 years. We carried out a complete sequencing analysis to screen all TPMT variants in pediatric patients and assessed the clinical manifestations including adverse drug reactions (ADR), WBC counts and optimal AZA dose in TPMT variants.
Results: TPMT variants were detected in 12 among 293 patients (4.1%). TPMT∗3C was found in 9 patients (3.1%): 8 patients (2.7%) with TPMT∗1/∗3C and one (0.3%) with TPMT∗3C/∗3C. Rare TPMT variants including TPMT∗6 and TPMT∗16 were detected in three patients (1.0%). The patient with ∗3C/∗3C mutation had prominent leukopenia and required low dose of AZA, 0.18 mg/kg/day to maintain an optimal therapeutic range of 6-thioguanine nucleotide (6-TGN). Three of eight patients with ∗1/∗3C mutation had ADR such as leukopenia, rash and hair loss and one of two patients with ∗1/∗6 mutation had nausea. However, one patient with ∗1/∗16 mutation did not present any ADR.
Conclusions: TPMT∗3C was the most frequent TPMT variant and TPMT∗6 was the second most common. Although TPMT genotype could not completely explain the thiopurine-induced ADR, it could be helpful to examine TPMT genotypes before administering AZA. The results of our study will be useful for future clinical studies on TPMT pharmacogenetics and dosage adjustment in the Asian IBD population.
251 MUCOSAL MICROBIOTA PROFILE IN NEWLY-DIAGNOSED CROHN'S DISEASE; DATA FROM A MIDDLE EASTERN PEDIATRIC POPULATION
Mohammad El Mouzan1, Mohammed Al Mofarreh2, Ahmad Al Sarkhy1, Ahmad Al Barrag1, Rajita Menon3, Assad Assiri1, Mona Al Asmi1, Kirill Korolev3, Anjum Saeed1, Harland Winter4, Yassin Hamid1,1King Saud University, Riyadh, Saudi Arabia,2Al Mofarreh Polyclinics, Riyadh,, Saudi Arabia,3Boston University, Boston, Mass, USA,4Mass General Hospital for Children, Boston, MA, USA
Background and objective: Most reports on the the microbiome in Crohn's disease (CD) are from Western populations.
Objective: To evaluate the gut microbiota in a population of children from Saudi Arabia.
Patients and Methods: All children were Saudi nationals from 0.5 to 17 years of age at presentation. The diagnosis of CD was confirmed according to standard criteria. Controls were children who had a normal colonoscopy and no infection. Colonic mucosal samples (25 CD and 11 controls) were immediately frozen in – 800 C. Samples were shipped in dry ice to MR DNA, Shallowater, TX, USA where Amplicon pyrosequencing (bTEFAP®) was performed using 16 S primers. Bioinformatic analysis was performed to assess microbial diversity as well as genera and species associated with CD.
Results: There was a significantly reduced bacterial alpha diversity in CD mucosa (Shannon index p
= 0.010). There were significant species reduction of certain bacterial genera (ruminiclostridium; p
= 0.00001) and species (eubacterium siraeum; p
= 0.00001, q 0.003, Dialister spp; p
= 0.000031, q 0.0058) in CD. This pattern parallels previous findings on CD in Western microbiota. Overall, we found the mucosal microbiota profile similar between Western and this Middle East population in both health and disease, suggesting a minor effect of ethnicity and lifestyle.
252 UNDERSTANDING THE PATHOGENIC ROLE OF TETRATRICOPEPTIDE REPEAT DOMAIN 7A IN CAUSING VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE THROUGH ITS BINDING PARTNER, E3 UBIQUITIN LIGASE UBR5
Neel Dhingani, Conghui Guo, Neil Warner, Ryan Murchie, Aleixo Muise, The Hospital for Sick Children, Toronto, ON, Canada
Background: Inflammatory bowel disease (IBD) is on the rise in infants as well as children and the genetic factors show a more prominent role in causing the disease for very early onset IBD patients. Patients with mutations in the Tetratricopeptide Repeat Domain 7A (TTC7A) result in an untreatable IBD and the majority die before 2 years of age. TTC7A mutation(s) produce spectrum of intestinal diseases such as apoptotic enterocolitis to multiple intestinal atresia with combined immunodeficiency. Pathological feature of these patients show disrupted apicobasal polarity. TTC7A's role in cellular function is unknown and can be elucidated through identifying its binding partners to reveal its pathway of action. Recent data have shown that TTC7A is part of an evolutionarily conserved complex where it acts as a scaffolding protein by recruiting PI4KIIIa to the plasma membrane and through EFR3B, PI4KIIIa is involved in generating PI4P. PI4P's levels at the plasma membrane have been implicated in cell survival and the maintenance of cell polarity. Mass spectrometry results from our lab has shown E3 ubiquitin ligase UBR5 as one of the potential interactors of TTC7A. Previous research with UBR5 has shown to interact with β-catenin to up-regulate Wnt signaling. I hypothesize that UBR5 binds to PI4KIIIa-TTC7A-EFR3B to form a molecular complex to maintain the apicobasal polarity. Mutation(s) in the TTC7A results in a defective TTC7A protein, disrupting the complex and consequently losing the apicobasal polarity of the cellular tissue.
Methods: The HEK 293T cells were co-transfected with appropriate plasmid and were then harvested and lysed. Co-immunoprecipitation (co-IP) was performed with the lysates to pull down either the UBR5, TTC7A or PI4KIIIa, followed by Western blot analysis.
Results: My preliminary results have shown the interaction between the UBR5 and TTC7A wild-type and the mutants (E71K, A832T and Q526X) through co-IP and Western blot analysis. Another set of preliminary results show an interaction between PI4KIIIa and UBR5.
Conclusion/Future directions: Overall, this work aims to elucidate the pathogenic role of TTC7A in disrupting apicobasal polarity through its interaction with the binding partners. Once the interactions are confirmed between the UBR5, PI4KIIIa and TTC7A variants through additional co-IP experiments, functional studies will be done to understand the pathogenesis of TTC7A. This will be done by knocking out TTC7A using shRNA. The Western blot will also be used to test for apicobasal polarity markers to find out if UBR5-TTC7A mutant interaction has an impact on apicobasal polarity. Immunofluorescence studies will be performed to find the localization of UBR5 and TTC7A variants within the cell. We hope that further understanding the role of TTC7A and its binding partners will lead to the discovery of novel therapies for patients with these mutations as well as other IBD patients.
253 A RANDOMIZED, PLACEBO-CONTROLLED TRIAL OF FECAL MICROBIAL TRANSPLANTATION FOR PEDIATRIC ULCERATIVE COLITIS (PEDIFETCH TRIAL)
Nikhil Pai1, Jelena Popov1, Christine Lee2,1McMaster Children's Hospital, McMaster University, Hamilton, ON, Canada,2St Joseph's Healthcare, McMaster University, Vancouver, BC, Canada
Purpose: Previous studies have demonstrated therapeutic benefit of fecal microbial transplant (FMT) in ulcerative colitis (UC). This is one of the first randomized, placebo-controlled trials of FMT in pediatric UC and inflammatory bowel disease unclassified (IBD-U). We are testing the hypothesis that retention enemas containing live, fecal bacteria from unrelated, healthy human donors can improve disease activity.
Methods: Patients 6–17 yo with active UC or IBD-U, and stable pre-existing medications, were randomized to biweekly normal saline (placebo) or fresh-frozen stool (intervention) enemas over 6 weeks. Clinical response was assessed through the Pediatric UC Activity Index (PUCAI). Mucosal inflammation was measured through serial fecal calprotectin and blood samples. Microbial profiling was conducted on donor and patient stools via 16 s rRNA sequencing.
Results: Recruitment opened November 2015 and is ongoing. 19 patients were approached. 5 enrolled, 10 requested participation but did not meet eligibility criteria, and 4 declined participation. 2 patients (P001/P004) were randomized to intervention, and 1 patient (P002) to placebo. P001 stopped treatment after 8 enemas due to disease flare at week 4; fecal calprotectin showed improvement (1024 μg/g baseline; 578 μg/g week 3). P004 showed improvement in fecal calprotectin (3462 ug/g baseline; 744 ug/g week 3), and CRP (3.1 mg/L baseline; 0.4 mg/L week 6). P002 showed improvement in PUCAI score (15 baseline; 0, week 6), and fecal calprotectin (607 μg/g baseline; 38 μg/g week 6); at week 10, PUCAI score (30) and fecal calprotectin (1234 μg/g) increased. Results for 2 additional patients are pending. α-diversity increased over treatment in the placebo arm, and in 1 patient from the intervention arm (Shannon-index, difference from baseline: 0.82; 0.21; -0.29). Bacterial taxonomy from the placebo arm showed decreased abundance of Bifidobacteria, Clostridium (Firmicutes), and increase of Faecalibacteria. The intervention arm showed similar decreased abundance of Bifidobacteria, but also a decrease in Faecalibacteria, and increase in Clostridium (Firmicutes). Mean α-diversity of healthy donor stools was lower than study patients at baseline (Shannon-index: 3.24 donor stool; 3.585 patient stool). Taxonomy of healthy donors showed enrichment of Ruminoccocus, Blautia, and Faecalibacteria. Patients in the intervention arm did not increase abundance of these genera with treatment.
Conclusions: Preliminary results demonstrate significant patient interest in FMT for UC/IBD-U. Two patients in the intervention arm showed improvement in disease activity, with one withdrawing due to a disease flare despite improvement in mucosal healing. Bacterial profiling shows variability in α-diversity and taxonomic richness at baseline, and over the course of treatment in placebo, and intervention arms. Ongoing recruitment and data collection will further delineate the therapeutic role of FMT in pediatric UC and IBD-U.
254 ASSESSING READINESS FOR TRANSITION IN ADOLESCENTS AND YOUNG ADULTS WITH INFLAMMATORY BOWEL DISEASE
Noel J. Jacobs, Jamie Travis, John Grunow, Oklahoma University Health Sciences Center, Oklahoma City, OK, USA
More than 30 percent of youth 10 to 17 years of age have a chronic illness. Previous research has linked poorly managed transfer to adult care of patients, including inflammatory bowel disease (IBD) patients, to treatment nonadherence, loss to follow-up, increased disease severity, emergency hospitalizations and excessive stress for patients, families, and providers. Numerous medical organizations have highlighted the need for adolescents and young adults (AYAs) to receive coordinated care from an interdisciplinary team to provide individualized planning and skill development for transition readiness. In order to understand the level of progress toward medical self-management in adolescence and young adulthood in a clinic for inflammatory bowel disease, 25 youth between the ages of 15 and 21 completed the Transition Readiness Assessment Questionnaire (TRAQ) as a part of routine comprehensive care. Eight patients completed the TRAQ more than one time to assess change in transition readiness throughout the course of intervention. The TRAQ is a reliable and valid 20-item self-report measure which assesses healthcare self-management skills in AYAs.
Preliminary results indicated that IBD patients completing the TRAQ for the first time, with a mean age of 17 years, typically scored in the range indicating some learning (“I am currently learning to do this”) about adult medical self-management responsibilities (M 3.50, SD 0.86). Patients indicated relative strength in talking with providers (M 4.68, SD 0.80), but relative weakness with appointment-keeping responsibilities (M 2.89, SD 1.13). Overall, higher scores were related to older age, being female, and having private insurance. Results also appear to indicate that, over time, patients move toward readiness, indicating benefit in routine assessment and the interventions to help them move forward. Implications of these findings, limitations, and future directions for transition readiness education and intervention for youth with IBDs will be discussed.
255 FLAXSEED IN A LOW-FAT DIET EXACERBATES CITROBACTER RODENTIUM-INDUCED COLITIS IN MICE
Pekka Maattanen1, Philip M. Sherman1, Eberhard Lurz1, C. William Yeung1, Richard Y. Wu1, Bo Li1, Sumayyah Abiff1, Kathene C. Johnson-Henry1, Agostino Pierro1, Krista A. Power2, Marc E. Surette3,1Research Institute, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada,2Guelph Research and Development Centre, Agriculture and Agri-Food Canada, Guelph, ON, Canada,3Université de Moncton, Moncton, New Brunswick, Canada
Background: Flaxseed is a rich source of α-linolenic acid, fiber, and lignans, and has been shown to protect against colorectal cancer. However, the role of flaxseed as a dietary supplement for use in the management of inflammatory bowel disease is controversial.
Objective: To test the impact of flaxseed in a murine model of infectious colitis.
Methods: Three-week-old C57BL/6 mice just post-weaning were separated into four diet groups and fed either a high-fat diet (36% kcal from fat; HF) or low-fat diet (12% kcal from fat; LF) or isocaloric high or low-fat diets supplemented with 7% w/w whole ground flaxseed (36% kcal from fat with flax; HF Flx) or (12% kcal from fat with flax; LF Flx). After 4 weeks of feeding, mice in each diet group were either infected with 10^8 CFU of Citrobacter rodentium or sham infected by oral gavage (n = 8–10). Weights were monitored and stools collected during the course of infection. Mice were sacrificed 10–14 days post infection. Distal colons were examined for mucosal inflammation, epithelial cell proliferation, and pathogen colonization. Impact of flaxseed ingestion on levels of liver and intestinal tissue polyunsaturated fatty acids (PUFA), gut microbial diversity, and cecal pH and short-chain fatty acids were measured. Statistical analyses were performed by ANOVA with Tukey's multiple comparison test.
Results: LF Flx fed mice lost weight and HF Flx fed mice showed impaired weight gain after infection with C. rodentium, despite significant increases in liver and intestinal n-3 PUFAs. LF diet protected against C. rodentium-induced colonic crypt epithelial cell hyperplasia compared to HF diet (mean crypt length ± SEM; 162 ± 11 μm, vs. 219 16 μm, p < 0.01), decreased pro-inflammatory cytokine levels (TNFα, IL18, and IFNγ), and promoted more rapid clearance of the enteropathogen. By contrast, the LF Flx diet exacerbated colitis compared to the LF diet, with increases in epithelial cell hyperplasia (mean crypt length ± SEM; 231 ± 16 μm, vs. 162 ± 11 μm, p < 0.01), infection-induced expression of IL17α and IL22, and persistence of C. rodentium colonization. Relative to the LF diet, the LF Flx diet increased γ-proteobacteria and decreased Akkermansia muciniphila independent of infection. The negative effects of flaxseed in the LF Flx diet were apparent despite the fact that flax promoted an increase in microbial diversity, cecal short-chain fatty acids, and a decrease in cecal pH.
Conclusions: These data indicate that whole ground flaxseed exacerbates colitis in the setting of a low-fat diet and did not improve inflammation in a high-fat diet. The results serve to explain divergent effects of whole flaxseed supplementation in previous evaluations. These data also show that a low-fat diet lowers intestinal inflammation in response to C. rodentium and promotes rapid clearance of the enteropathogen from stool and colon tissues.
256 GM-CSF ANTIBODIES AND PERIPHERAL TREG CELLS AS POTENTIAL MARKERS OF THERAPEUTIC RESPONSE IN PEDIATRIC INFLAMMATORY BOWEL DISEASE
Piyali Ray1, Fernando Navarro1, Yuying Liu1, Lee A. Denson2, Cynthia S. Bell1, Nicole Fatheree1, Thomas Hoang1, J. Marc Rhoads1,1University of Texas Health Science Center at Houston, Houston, TX, USA,2Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
Introduction: The majority of adults with IBD respond to first line medications for remission. However, pediatric IBD is often associated with a more severe presentation, where aminosalicylates or steroids are ineffective in inducing remission, requiring more potent medications like biologics, with subsequent increase in cost and potential adverse effects. This study aims to measure non-invasive biomarkers, specifically GM-CSF antibodies and peripheral Treg cells, during induction of remission in pediatric IBD. Hypothesis: GM-CSF antibodies are present in high titer in more severe IBD in association with reduced intestinal GM-CSF bioactivity and increased intestinal permeability. Foxp3+ Treg cells are present in low titer in peripheral blood of patients with severe IBD, indicating a primary immune dysregulation, in which an inherently reduced Treg cell population is incapable of downregulating the immune response.
Methods: Blood collected before treatment was analyzed for GM-CSF antibodies by ELISA and peripheral Tregs by flow cytometry. Patients were followed prospectively to assess response to first-line medications versus step-up to biologics. GM-CSF antibodies, peripheral Tregs, and fecal calprotectin were monitored in patients during remission. PCDAI and PUCAI were scored to assess clinical improvement. We enrolled 28 patients with IBD of which 18 completed the study with pre- and post- treatment samples. Wilcoxon Rank Sum tests were used to compare baseline values between groups and Paired Signed-Rank tests used to compare pre- and post-treatment values. A two-sided p-value of 0.05 was considered significant.
Results: Median GM-CSF antibodies were higher (0.50 vs. 0.37) and Tregs lower (5.23 vs. 6.71) in the biologic cohort but no significant difference was found between initial GM-CSF antibody and Treg levels of patients requiring first-line versus biologics for remission (p 0.75 and p
= 0.62 respectively). In the biologic cohort, 37.5% showed decrease in GM-CSF antibodies and 75% showed increase in Tregs after treatment but the % change was not significant (p 0.42 and p
= 0.37, respectively). There was a trend toward higher GM-CSF antibodies in the CD versus UC group (0.81 vs. 0.31, p
= 0.073). Activity indices showed significant improvement in the biologic cohort only in UC (p 0.04).
Conclusions: Two new biomarkers may add value to the existing non-invasive biomarkers to guide management strategies in IBD and monitor response to therapy. No individual biomarker was able to reliably predict need for biologics in this study. Further studies are needed to develop a predictive model using a combination of biomarkers that may help identify the most effective treatment in pediatric IBD to reduce hospitalizations, healthcare cost and increase the chance of a steroid-free remission.
257 BUILDING A CLINICAL AND RESEARCH DATABASE FOR CHILDREN WITH INFLAMMATORY BOWEL DISEASE (PEDIDATA): A STEP-BY-STEP PROCESS
Prevost Jantchou, Sainte Justine Hospital, Montreal, QC, Canada
Background: Quality of care is important for children with Inflammatory Bowel disease (IBD). Recently various quality indicators have been identified by scientific societies to assist and guide the management of IBD patients. But the monitoring of these indicators implies a systematic process of data collection and update. Many hospitals use paper based medical records or electronic medical record not designed for collecting and updating these indicators. Some initiatives like ImproveCareNow (ICN) project in the United States have demonstrated a benefit of a quality improvement (QI) process in the follow-up of children with IBD. In 2012, we initiated a process of creating a database to prospectively follow our large cohort of children with IBD.
Objective: The aim of the present work is to share the various steps toward building the database, the usability and the clinical and research usefulness.
Methods: Sainte Justine Hospital is a tertiary hospital in Quebec. The gastroenterology unit comprises 10 senior physicians, 6 fellows, and 1 nurse dedicated to IBD patients. Each year, 90–100 new cases of IBD are diagnosed in our unit. The active cohort comprises approximately 500 patients. PediData is a prospective database that was built from scratch following various steps following of the plan-do-study-act (PDSA) cycle: (1) literature review, (2) focus group (3) choice of the software (4) drafting of the first version of the software (5) diffusion (6) validation (5) evaluation of usefulness.
Results: We chose Filemaker Pro software version 14 because of its usability and functionality on multiple platforms: Windows, Mac, tablets. The final version of PediData includes different sections organized in tabs: administrative, imaging, treatment, follow-up, lab results. This database is hosted internally in a server in our hospital and access is granted by a private password for each user (physician, nurse, dieticians). From January 2013 to December 2015, there was a total of 287 new cases of IBD (154 male; 183 Crohn's disease, 60 ulcerative colitis, 44 indeterminate colitis). The database enabled us to identify the following baseline quality indicators: rate of children treated with corticosteroid/enteral nutrition (at diagnosis), anemia, transfusion, hospitalization, emergency visits, remission etc. Medication logs and lab results logs were two useful functionalities that enhanced the usefulness of the database. With PedData search fields, we are able to easily identify children with specific characteristics for research purpose.
Conclusions: PediData gives a synoptic view of each patient and the whole IBD cohort. We have noticed a usability of the database with ease of data recording. PediData is part of a quality improvement process established in our hospital and will be a useful tool to track changes in quality indicators. The PediData structure could be easily shared with other centers.
258 INTERDISCIPLINARY QUALITY IMPROVEMENT APPROACH TO IMPLEMENTATION OF SCREENING, EVALUATION AND FOLLOW-UP FOR DEPRESSION IN YOUTH WITH INFLAMMATORY BOWEL DISEASE AND DIABETES
Rachel Bensen, Esti Iturralde, Molly Tanenbaum, Debbi Friedman, Katherine Shaw, Megan Christofferson, Sarah Hanes, Avni Shah, KT Park, Korey Hood, Stanford University School of Medicine, Palo Alto, CA, USA
Background: Adolescence is a high-risk period for behavioral health concerns and suboptimal self-management of chronic disease. Symptoms of depression have been shown to negatively impact disease management and health outcomes in chronic illness, including inflammatory bowel disease (IBD) and type 1 diabetes.1–3 Guidelines from the U.S. Preventive Services Task Force and professional organizations call for routine screening for depression in adolescents with systems to ensure accurate diagnosis, effective treatment, and appropriate follow-up.4 However, gaps exist and untreated depression leads to decreased adherence to therapy and adverse health outcomes.
Methods: Using a quality improvement approach, we aimed to create, implement and test a process for depression screening, assessment, and follow-up for youth (age > 12 years) with IBD and diabetes in a large pediatric specialty center. Our interdisciplinary team included GI and endocrine physicians, social workers (SW), psychologists and our IBD center coordinator. Depression was assessed with a validated measure, the Patient Health Questionnaire (PHQ)-9.5. A PHQ-9 score of >10, suggestive of moderate to severe symptoms, or a positive response to the suicidal ideation (SI) item triggered a real-time assessment by a psychology fellow or social worker. When needed, behavioral health services were established with the psychology fellow or support provided in identification of outside services with phone follow-up to identify and address barriers. For the initial implementation, patients were screened during one half-day clinic session per week. Resource utilization was tracked to inform expansion.
Results: Thirty-three patients were screened with diagnoses of Crohn's disease (n = 5), ulcerative colitis (n = 7), IBD unclassified (n = 1) and diabetes (n = 20). See Table 1 for demographics. Within IBD, 2 patients (15%) had moderate to severe disease on physician global assessment at the time of screening. Eight out of 13 were on treatments with biologics, representing underlying moderate to severe disease. Nine patients required same-day assessment for positive score on the PHQ; 6 diabetes (30%) and 3 IBD (23%). One patient endorsed SI with a PHQ <10. All ten received same-day assessments with a clear plan for follow-up. Patients with positive screens required 45 minutes of psychologist or SW time for assessment, referral, communication with the medical team, and documentation. Clinic flow was not disrupted.
Conclusions: Implementation of depression screening into routine pediatric specialty care is feasible using an interdisciplinary team and quality improvement framework. Integrating processes to address the identified behavioral health needs is essential to reduce barriers to adherence and improve health outcomes for youth with IBD and diabetes. Next steps include expansion to screen all youth in our centers and assessment of other patient reported outcomes.
259 CONCEPTUALIZING SUMMER CAMP AS A PSYCHOSOCIAL INTERVENTION: SIGNIFICANT IMPROVEMENT IN EMOTIONAL FUNCTION AND HEALTH-RELATED QUALITY OF LIFE AFTER PARTICIPATION IN A SUMMER CAMP FOR YOUTH WITH IBD
Rachel Lawton1, Robert Rothbaum2, Michelle LaRose-Wicks3, Jill Weissberg-Benchell4, David Victorson5, Jason Washburn6,1Yale Child Study Center, New Haven, CT, USA,2St. Louis Children's Hospital, St. Louis, MO, USA,3Crohn's and Colitis Foundation of America, St. Louis, MO, USA,4Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA,5Northwestern University Feinberg School of Medicine, Evanston, IL, USA,6Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Background: Summer camp has long been conceived as a possible psychosocial intervention for pediatric patients with chronic illness. While research has explored the efficacy of these experiences among patients with a wide range of pediatric diagnoses (including hematology/oncology, HIV/AIDS, burn-victims, diabetes, and Celiac disease), research that has explored the significance of summer camp for pediatric patients with IBD is scarce. This research aimed to explore the psychosocial implications of participation in a summer camp specifically for youth with IBD.
Methods: Researchers completed a prospective, longitudinal, single cohort study. Participants were recruited from a cohort of patients registered to attend an overnight summer camp for children and adolescents with IBD. Questionnaires were completed online 2 weeks prior to camp participation and 2 weeks thereafter. Study measures assessed psychosocial function, health-related quality of life, post-traumatic growth, social connectedness, and loneliness. All measures were validated with sound psychometric properties.
Results: Twenty-eight participants and their parents completed all study measures. Fifty-nine percent of participants were male and mean participant age was 13.5 years. Sixty-eight percent of participants had a prior Crohn's disease diagnosis. At baseline, prior camp participants reported significantly less avoidance of IBD-related thoughts and significantly greater emotional function than participants with no prior experience. At post-camp assessment, there was a significant reduction in psychosocial symptoms following participation in camp (t (27) 2.6, p = .02, d = .50). Post-camp total health-related quality of life was significantly greater than the total health-related quality of life reported prior to camp (t (27) -2.4, p
= .02). Campers also reported significant improvements in individual health-related quality of life subscale measures including emotional function, school function, and general psychosocial health. All improvements reflected a moderate effect size. Campers reported significantly greater personal strength related to their IBD diagnosis after camp participation than prior to it (Z = -2.1, p
Conclusion: Camp can, and should, be conceptualized as a successful psychosocial intervention that provides pediatric patients with an unprecedented opportunity to surround themselves by peers with shared experiences. This environment appears to act as an exposure, reducing the pediatric patient's need to avoid reminders of illness and subsequently increasing their emotional function, health-related quality of life, and sense of personal resilience. Physicians and caregivers should strongly consider the importance of camp participation and the potential psychosocial gains that it may afford, particularly for patients who are at risk for poor psychosocial function or who have limited exposure to/experience with other pediatric IBD patients.
260 INTRAVENOUS IRON SUCROSE FOR ANEMIA ASSOCIATED WITH PEDIATRIC INFLAMMATORY BOWEL DISEASE
Ramy Sabe, Anant Vatsayan, Ali Khalil, Sanjay Ahuja, Thomas J. Sferra, University Hospitals Rainbow Babies & Children's Hospital, Cleveland, OH, USA
Background: Anemia is a common extra-intestinal manifestation in children with inflammatory bowel disease (IBD). Oral iron therapy is widely used and patients tend to have poor compliance due to side effects, especially the gastrointestinal ones. Intravenous iron therapy was shown to be safe and efficacious in adult patients with IBD, but has not been well studied in children. We use Intravenous Iron Sucrose (IVIS) at our institution for iron deficiency anemia (IDA). We hypothesized that IVIS is safe and efficacious in children with IBD as it is in adults. Therefore, we conducted a retrospective review investigating the safety and efficacy of IVIS in for IDA in pediatric IBD.
Methods: We reviewed the inpatient and outpatient medical records at our institution of all IBD patients 21 years of age or less who received IVIS between July 1,2009 and October31,2014. The diagnosis of anemia was based on blood hemoglobin (Hgb) level below the normal range for age and sex. IDA was identified based upon serum iron studies and red cell mean corpuscular volume. Each IVIS administration was evaluated for safety (any adverse reaction). Efficacy was defined as a ≥2 g/dL increase in Hgb level at 4, 8 or 12 weeks following the initiation of the IVIS course (a course might consist of one or more infusions). Normally distributed data are reported as mean ± standard deviation (SD) and non-normally distributed as median with interquartile range (IQR).
Results: We identified 88 patients with IBD (Crohn's disease, n = 52; ulcerative colitis, n = 33; and IBD-undetermined, n = 3) who underwent IVIS infusions during our study period. The female to male ratio was 1.1:1. The median age at the time of infusion was 15 years (IQR 12 ̈C 17 years, range 1–21 years). The majority (n = 67) of patients received one course of IVIS, 14 patients received two, 3 received three, 3 received four, and 1 received five. 121 courses of IVIS were evaluated. The median number of infusions per course was 3 (IQR 2 ̈C 3, range 1 - 14 infusions). The median dose per course was 365 mg (IQR 200 ̈C 600; 7.0 mg/kg, IQR 4.0 ̈C 12.2). No patient developed anaphylaxis. Minor adverse reactions occurred in 6 patients; none required discontinuation of the IVIS infusion. Out of the 121 IVIS courses, 40 were excluded from the efficacy evaluation due to a recent blood transfusion, incomplete clinical data, or non-IDA. Overall 58% (47/81 courses) resulted in the goal therapeutic increase in Hgb (24 courses by 4 weeks; 15, 8 weeks; 8, 12 weeks). There was a significant rise in Hgb for all 81 courses from a mean of 9.1 (SD 1.45) to 11.8 g/dL (SD 1.77; p < 0.0001, paired t-test).
Conclusion: IVIS is safe as only a few mild adverse events were observed. Furthermore, IVIS appears to be an efficacious treatment for IDA in pediatric IBD patients. The observed rise in hemoglobin was significant for all evaluated IVIS courses, with the majority achieving the goal Hgb.
261 UTILITY OF FECAL CALPROTECTIN IN THE ROUTINE EVALUATION OF CHRONIC GASTROINTESTINAL COMPLAINTS IN CHILDREN IN THE PRIMARY CARE SETTING
Ramya Ramraj1,2, Amy Garcia2, David Mosen1, Lisa Waiwaiole1, Ning Smith1,1Kaiser Permanente Center for Health Research,2 Oregon Health and Sciences Universit, Portland, OR, USA
Background: Evaluation of chronic gastrointestinal symptoms in children and differentiating between organic and non organic causes can often be a diagnostic challenge. Fecal calprotectin is now a well-recognized non invasive marker of Inflammatory Bowel Disease (IBD). It is routinely used in the evaluation of chronic gastrointestinal complaints to screen patients for possible IBD and further evaluation with endoscopy. However, only limited data is available regarding the utility of routine fecal calprotectin testing for evaluation of chronic GI symptoms in the primary care setting.
Methods: Charts of all patients between the ages 0–21 who had a fecal calprotectin between the years 2010–2014 were identified through an electronic pull from the Kaiser NW Permanente database. The age at time of testing and calprotectin values were also obtained. Each chart was then individually reviewed to identify the primary indication for testing and the outcome in the subsequent 12 months from the time of testing.
Results: Between 2010–2014, there were a total of 822 patients in the age group 0–21 who had a fecal calprotectin test without a known diagnosis of IBD and at least a year follow-up. Abdominal pain was the primary indication in 532 patients. Other primary indications included diarrhea (115), blood in stool (95), poor weight gain/ weight loss (44), nausea and vomiting (16) and anemia (4). Other miscellaneous causes include rectal pain (5), fistula (2), GERD (4), constipation (2), canker sores (2) and allergies (1). 689/822 (84%) patients had normal fecal calprotectin values of <162.9 ug/gm (Quest Laboratories). In the subsequent 12 months, 14 underwent endoscopies and biopsies were normal; 12 received other diagnoses including EoE, celiac disease, polyp and H. pylori; 663/822 patients did not receive a diagnosis of IBD and no concerning symptoms or red flags were documented in subsequent visits that could indicate presence of missed IBD.
133/822 (16%) patients had elevated fecal calprotectin (>162.9 ug/gm); 42/133(31%) received diagnosis of IBD with histologic confirmation, 18/133 received other diagnoses including Clostridium difficile infection, Celiac disease, E Coli, Salmonella, giardiasis, H. pylori, Cystic Fibrosis, milk protein sensitivity, Henoch Schonlein Purpura and polyps. 5/133 had normal endoscopies and biopsies. 39/133 had repeat fecal calprotectin tested in the next 12 months that returned to normal; the remaining 29/133 patients had resolution of symptoms in the next 12 months. Mean calprotectin values for the IBD vs. non IBD groups were 1206 ± 106.5 vs. 74.53 ± 5.9 (p < .0001). Sensitivity and specificity analyses were done (Table 1).
Conclusion: Based on this cohort, fecal calprotectin has 100% sensitivity in detection of IBD. Thus it is an excellent tool in the primary care setting to exclude IBD and avoid unnecessary referrals and endoscopies.
262 PREVALENCE OF DUODENAL PATHOLOGY IN PEDIATRIC CROHN'S DISEASE
Rebecca Casini, Valentina Shakhnovich, Moo Cho, Vicki Fioravanti, Vivekanand Singh, Children's Mercy Hospital, Kansas City, MO, USA
Introduction: The duodenum is a major site of drug absorption for perorally administered (PO) medications. Recently published data from our group suggest decreased expression of proteins and enzymes important to drug disposition (e.g. CYP3A4) in inflamed vs. non-inflamed duodenum of children with CD. The prevalence of duodenitis in children with Crohn's disease (CD) is reportedly higher than the estimated 28% in the adult CD population; however, existing pediatric studies are limited by small sample size. Accurate information regarding the prevalence of duodenal disease in children with CD is important, as many of these patients are treated with PO drugs (e.g., prednisone, azathioprine), which are susceptible to first-pass metabolism in the duodenum.
Objective: The aim of this descriptive study was to determine the prevalence of duodenal pathology in pediatric CD.
Methods: Retrospective data from a clinical database at The Children's Mercy Hospital (CMH) was reviewed to assess prevalence of duodenitis in patients with CD who received care at CMH between January 2002 and April 2010 (n = 577). In an independent cohort (n = 32), prevalence of duodenal pathology was prospectively assessed in children with CD who underwent endoscopy at CMH between September 2014 and April 2016.
Results: Of the patients treated for CD in 2002–2010, 313 were specifically evaluated for duodenitis. Of these, 222 (71%) were diagnosed with duodenitis. In the prospective CD cohort, duodenal pathology was confirmed by gross endoscopy, histopathology, and/or imaging in 15 of 32 children (47%).
Conclusions: The prevalence of duodenal pathology in children with CD is higher than what has been previously reported in adults. Duodenal disease may be an important factor to consider in pediatric CD phenotypes. Studies are ongoing to investigate duodenal pathology as a source of variability in disease outcomes and treatment response in children taking PO medications for the treatment of CD.
∗263 MUCOSAL MICROBIOME RESPONSES IN PEDIATRIC ULCERATIVE COLITIS DURING IMMUNOTHERAPY AND FECAL MICROBIOTA TRANSPLANTATION
Richard Kellermayer1,2, Dorottya Nagy-Szakal1,2, Deborah Schady1,2, Texas R. Alan Harris2, Scot E. Dowd3, Emily Hollister1,2,1Texas Children's Hospital, Houston, TX,2Baylor College of Medicine, Houston, TX, USA,3Molecular Research, Shallowater, TX, USA,
Background: Disturbed gut microbiome-mucosa interactions are thought to be critical in the pathogenesis of inflammatory bowel diseases (IBD: Crohn's disease (CD) and ulcerative colitis (UC)). IBD is a precancerous condition linking microbiome-related-inflammation with enterocyte/epithelial proliferation.
Objectives: We aimed to examine an unprecedented compendium of specimens from pediatric UC patients with respect to microbiome-mucosa interactions based on high-throughput methodologies.
Methods: Serial rectosigmoid biopsy samples were collected from 3 pediatric UC patients suffering from pancolitis at diagnosis (treatment naïve [TN]), during remission under immunotherapy (IT), and following fecal microbiota transplantation (FMT) without IT. Microbiome composition was evaluated by 454 based 16S rRNA pyrosequencing. Log-transformed bacterial abundances were paralleled with RNA-sequencing based mucosal gene expression changes between the IT and FMT specimens.
Results: Between diagnosis (TN) and immunotherapy induced remission (IT), increase of abundance occurred in Bacteriodes vulgatus (average 0 to 14.83%), and Faecalibacterium prausnitzii (0.08 to 5.56%) among others, while Ralstonia picketii decreased the most (8.51 to 0.02%) (Table 1). Log-transformation augmented the significance of these changes. Following the FMT series, Enterorhabdus spp. and Roseburia spp. increased in abundance among others (Table 1). Log-transformed abundance changes of these species, however, had the largest number of significant (Pearson correlation p≤0.048) mucosal gene suppression correlations. Twenty-eight percent (28%) of the genes responsive to FMT correlated with the abundance shifts of both bacterial species. The 289 common, Enterorhabdus spp. and Roseburia spp. responsive genes were significantly enriched in functional roles related to nucleotide binding and cell cycle control. The mucosal gene and microbiome changes secondary to FMT associated with decreased epithelial mitosis/proliferation in the UC patients.
Conclusions: Our findings suggest that microbiome-based treatment strategies may provide added benefit for pediatric UC patients by modulating the precancerous nature of the disease through the suppression of epithelial proliferation.
264 IMPACT OF INITIAL TREATMENT STRATEGY ON SECONDARY LOSS OF RESPONSE TO INFLIXIMAB IN PEDIATRIC CROHNS DISEASE
Rishi Bolia, George Alex, Jeremy Rosenbaum, Vered Schildkraut, Donald Cameron, Winita Hardikar, Mark Oliver, The Royal Children's Hospital, Melbourne, Victoria, Australia
Introduction and Aims: The use of infliximab has significantly improved the management of Crohn's disease refractory to conventional therapies. Unfortunately, a number of children, after an initial response, develop a secondary loss of response (LOR). Whether the choices of the initial treatment agents have an effect on the subsequent outcome with regards to LOR to infliximab is not known. We studied the effect of initial treatment strategies on secondary LOR to infliximab.
Methods: In this single-center retrospective study we reviewed the medical records of children with Crohn's disease who had received scheduled maintenance infliximab therapy for at least 12 months. We compared children who developed LOR with those who did not, with regards to the different therapeutic modalities that they received before developing LOR.
LOR was defined as clinical relapse while on maintenance therapy requiring dose intensification or switching over to adalimumab therapy.
Results: 73 children (median age at diagnosis - 11 (2 – 16) years, 41 boys) who had received a median duration of 33 (13–110) months of infliximab therapy were enrolled. LOR was seen in 25 (34.2%) children after a median duration of 18 (8–48) months of therapy.
Children with LOR were compared with those who did not develop LOR. The disease clinical phenotype (age, disease location and behavior) and PCDAI at induction with infliximab was similar between both groups.
On comparing the treatment regimens between the two groups, there was no statistical difference in LOR rates between children in whom EEN [3/13 (23.07%)] or steroids [21/53 (39.6%)], p 0.34 was used as an induction agent. In 7 children with fistulizing Crohn's disease, infliximab was used as an induction agent at the time of diagnosis. On comparison of maintenance agents, LOR rates between those on thiopurines [12/43 (28%)] and methotrexate [13/30 (43.3%)], p 0.14 were similar. Majority of the children were on a concomitant immunomodulator [65/73) 89%] while on infliximab. The median time – lag between diagnosis and induction with infliximab was significantly longer in children with LOR as compared to those who did not have a LOR [28 (4–90) months vs. 12.5 (1 – 121) months, p 0.004]
Conclusion: Early use of infliximab in pediatric Crohn's disease leads to a decrease in secondary LOR.
265 THE HETEROGENEOUS PRESENTATION OF PANCREATITIS IN PEDIATRIC INFLAMMATORY BOWEL DISEASE
Ronen Stein, Judith Kelsen, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
Introduction: Pancreatitis is a known extraintestinal manifestation of inflammatory bowel disease (IBD), but the association between pancreatitis and IBD in the pediatric population is not well-defined.
Aim: To describe the characteristics and disease course of children with IBD who develop pancreatitis.
Methods: A retrospective chart review of all IBD patients up to the age of 21 years admitted to The Children's Hospital of Philadelphia for the diagnosis of pancreatitis between January 2011 and April 2016 was performed. Demographics, date of diagnosis, disease activity, medication and surgical history were recorded.
Results: there were 40 hospitalizations for the indication of pancreatitis among 26 children with IBD (16 with Crohn's disease, 5 with ulcerative colitis, and 5 with indeterminate colitis). Among the 16 children with Crohn's disease 11 (68.8%) were known to have disease in the duodenum. The mean age +/- SD at the first episode of pancreatitis was 14.5 +/- 3.5 years. Pancreatitis was the presenting symptom for 7/26 (26.9%) newly-diagnosed patients. The median lag-time between initial diagnosis of IBD and the first episode of pancreatitis was 0.6 (interquartile range 0.1, 2.4) years. Median Pediatric Crohn's disease Activity Index and Pediatric Ulcerative Colitis Activity Index scores were 17.5 (interquartile range 10.0, 25.0) and 22.5 (interquartile range 10.0. 45.0), respectively. Stool calprotectin was obtained within 3 months of a pancreatitis episode on 19 occasions and found to be elevated (>250 μg/g) in 13 cases (68.4%) with a median calprotectin of 453.0 (interquartile range 150.0, 1,250.0). IBD medications, including 5-aminosalicylates, methotrexate, sulfasalazine, and thiopurines, were identified as the likely cause of pancreatitis in 9/26 (34.6%) children and were discontinued. Recurrent pancreatitis occurred in 6 patients. No hereditary causes of recurrent pancreatitis were discovered on genetic testing among these patients, although 1 patient was later diagnosed with autoimmune pancreatitis and another was found to have pancreatic divisum. Two patients were found to have imaging findings consistent with chronic pancreatitis. Neither pancreatic necrosis nor pseudocyst formation was seen in this cohort.
Conclusion: Pancreatitis, an extraintestinal manifestation of IBD, can be the presenting symptom or occur early in the disease course. It may coincide with active disease in some patients with IBD. Future genomic discoveries may provide important insight regarding the association between pancreatitis and pediatric IBD.
∗266 BISPHENOL-A AT ENVIRONMENTAL DOSES INCREASES INTESTINAL PERMEABILITY AND INDUCES INFLAMMATION
Rossella Valentino, Merlin Nanayakkara, Ilaria Cimmino, Maria Vittoria Barone, Vittoria D’esposito, Fabiana Ariemma, Giusy Mosca, Valeria Tornatore, Riccardo Troncone, Francesco Beguinot, Pietro Formisano, Federico II University of Naples, Naples, Italy
Bisphenol-A (BPA), an obesogen endocrine disruptor, main plastic component, has a pro-inflammatory effect on adipose tissue and on immune system and is responsible for low-grade systemic inflammation associated with overweight and obesity. Humans are chronically exposed to BPA mainly via oral contact, through contaminated food and beverages. Considering that the prevalence of inflammatory bowel diseases(IBD) is rapidly increasing in the world and that the gut is the first point of contact for BPA, its effect on the intestinal barrier function can be suggested. We hypothesize that BPA acting during the maturation of intestinal barrier function against foreign agents, might be responsible for alteration in epithelial gut monolayer function and for the impairment of mucosal immune system and tolerance. Thus, the aim of this study was to investigate the BPA role, at low environmental doses, in the development of intestinal inflammatory diseases. To evaluate the effect of BPA on human intestinal barrier, human colon adenocarcinoma derived cells (Caco-2 cells) were grown in monolayers and challenged with 1 nM BPA during differentiation (20 days). The trans-epithelial electrical resistance (TEER) was used as index of monolayer integrity, with para-cellular solute flux measurement to monitor the permeability. The redistribution of tight junction (TJ) proteins was analyzed in cells cultured on coverslips and the examination was performed using a confocal laser microscopy (Zeiss 510 Meta Confocal Laser Scanning Microscope). Immune-precipitation and immune-blot analyses were employed to investigate the intracellular pathways. A panel of 27 different cytokines, chemokines and growth factors was determined in the culture supernatants using BIOPLEX multiplex Human assay kit (Bio-Rad, Hercules, CA,USA). At day 17 of differentiation, a significant TEER reduction (p < 0.01) was reported in cells upon BPA incubation compared to control cells. An alteration in TJ redistribution was confirmed at confocal microscopy observation, supporting the increased permeability of enterocyte monolayer. Moreover, activation of NFkB inflammatory pathway and a significant increase in Interleukin-7 (IL-7) and Monocyte Chemo-attractant Protein-1 (MCP-1/CCL2) secretion was observed upon BPA treatment.
In conclusion, at environmental low doses, BPA may induce alteration in gut barrier permeability via trans-epithelial and para-cellular flux variation, with deregulation of the TJ integrity and barrier function. These effects can be responsible for enhanced translocation of pathogenic molecules from the gut lumen to extra-intestinal sites, increasing the risk of impaired tolerance to food antigens and colonic inflammation in adult life. The BPA direct contact may cause activation of inflammatory pathways, with subsequently production of pro-inflammatory cytokines and probably inappropriate immune response in lamina propria.
267 METHOTHREXATE INDUCTION AND MAINTENANCE OF REMISSION IN PEDIATRIC INFLAMMATORY BOWEL DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS
Ruben J Colman1, Rachel Lawton2, Marla C Dubinsky3, David T Rubin4,1St. Barnabas Hospital, Bronx, NY, USA,2Yale Child Study Center, New Haven, Connecticut, USA,3Mount Sinai Hospital, NY, NY, USA,4IBD Center, The University of Chicago Medicine, Chicago, IL, USA
Background: Methotrexate (MTX) is an immunomodulator commonly used for the treatment of pediatric inflammatory bowel disease (IBD). However, while randomized controlled trials (RCTs) have demonstrated treatment efficacy for adult patients, there are currently no RCTs that assess the treatment efficacy of methotrexate within the pediatric IBD patient population. This systematic review and meta-analysis attempted to assess the efficacy of MTX therapy among the existing pediatric literature.
Methods: A systematic literature search was performed using MEDLINE and the Cochrane library from inception until March 2016. Abstracts from GI conferences were also searched. Synonyms for ‘pediatric’, ‘methotrexate’ and ‘IBD’ were utilized as both free text and MESH search terms. The studies included contained clinical remission (CR) rates for MTX treatment of pediatric IBD patients 18yrs old, as mono- or combination therapy. Case studies with less than 10 patients were excluded. Quality assessment was performed with the Newcastle-Ottawa Scale. Meta-analysis calculated pooled CR rates and distinguished between patient subgroups. A random-effects meta-analysis with forest plots was performed using R. X2 test and p < 10 level significance was used to assess for heterogeneity.
Results: Fourteen (11 monotherapy, 1 combination therapy, 2 both; n = 886 patients) observational studies were eligible out of 200 studies. No interventional studies were identified. The pooled CR rate for IBD patients on monotherapy within 12 months was 54.3% (95% CI, 45.2%-63.2%), with a moderate risk of heterogeneity (p 0.08; I2 = 44%). When ulcerative colitis (UC) was excluded, the achieved pooled CR rate for Crohn's disease (CD) was higher and very consistent among studies CR: 56.9% (95% CI, 50.1–63.5%), (p 0.46; I2 = 0%). The CR decreased to 35.4% (95% CI, 30.5–40.1%), (p 0.41; I2 = 0%) for maintenance therapy at 12 months since induction. Two studies assessed treatment efficacy for maintenance therapy 12 months after achieving CR, and demonstrated similar CR rates (31% and 42%). Sub-analysis could not identify CR differences between MTX administration types, thiopurine exposed vs. naïve (uOR 1.34 (95% CI, 0.72–2.49); p
= 0.35), thiopurine failure vs. intolerance (pooled OR 1.03 (95% CI, 0.51–2.06); p
= 0.31). Combination therapy outcomes were only described for 23 patients in 3 studies. One study assessed mucosal healing. Growth-velocity outcomes were described by 3 studies. Two UC studies were identified which showed lower rates for both induction as maintenance of remission.
Conclusion: This meta-analysis demonstrated that, within the published literature over 50% of pediatric IBD patients who are prescribed methotrexate achieved remission. Among pediatric CD patients, CR rates are highly consistent and demonstrate a remission rate of 57% for induction and 35% for 12-month maintenance. Prospective controlled interventional trials should assess treatment efficacy among patient subgroups.
268 VARIABLE LEVELS OF TRANSITION READINESS IN PEDIATRIC INFLAMMATORY BOWEL DISEASE (IBD) PATIENTS
Tolulope Falaiye, Marc Schaefer, Emmanuelle Williams, Vernon Chinchilli, Penn State Hershey, Hershey, PA, USA
Background: IBD patients diagnosed as children will need to transition to adult doctors. The process of transition from pediatric to adult care can be difficult. Poor transition can result in unfavorable outcomes such as increased hospitalizations. A pediatric IBD transition clinic was established to guide this process. In order to establish areas of need, a validated transition readiness assessment questionnaire (TRAQ) is administered to patients in the transition clinic.
Methods: Patients 17–18 years of age were referred to the transition clinic by their pediatric gastroenterologists. Our transition clinic is a 2-visit process. First, the patient is seen by a pediatric IBD specialist. At visit 2, a few months after, the patient is seen by an adult IBD specialist. The morning prior to the visit, pediatric and adult doctors meet to discuss transitioning patients. After the 2nd visit, the patient's care is transferred to adult IBD. Patients are given the TRAQ to complete at the beginning of their visit. TRAQ version 5 has 20 questions in 5 domains of care: managing medications, appointment keeping, tracking health issues, talking with providers and managing daily activities.
Results: From April 2014 through January 2015, 13 patients were seen in the transition clinic. In response to question 3, 12/13 (92%) patients reported always taking their medicines correctly on their own, while 1/13 (8%) reported learning to take their medicine. Question 9 asks if patients apply for health insurance. 3/13 (23%) patients responded they always apply, 2/13 (15%) are learning to apply, 3/13 (23%) want to learn and 4/13 (30%) reported not knowing how to apply. Question 12 asks if patients fill out the medical history form. 6/13 (46%) patients responded always, 5/13 (38%) have started filling out the form, 1/13 (8%) want to learn how to fill out the form and 1/13 (8%) do not fill out the medical history form. Transition readiness was found to be variable between the different domains, even within one individual. One patient's responses to the 20 questions in the TRAQ included 9 “always”, 1 “started”, 7 “learning”, 1 “want to learn” and 2 “I do not know how”. Overall, for some questions most patients reported high readiness, such as question 3. For other questions, there was much lower readiness and greater variability, such as question 9.
Conclusions: We found that the transition clinic is feasible and sustainable. The administration of TRAQ does not interfere with clinical care. Patients can have different levels of transition readiness. Patients reported high transition readiness in areas of managing daily activities and talking with providers. Transition readiness was lowest in the appointment keeping domain. The lowest median score was for the question “Do you apply for health insurance if you lose your current coverage?” Further study is needed to understand what factors affect different domains of transition readiness in order to improve transition care.
269 CELL DIVISION CYCLE 42 IS REQUIRED FOR GUT STEM CELL REGENERATION AND RESPONSE TO COLITIC INJURY
Wenjuan Tang1, Dongsheng Zhang2, Haitao Niu3, Ying Huang3, Shila Gilbert3, Richard Moriggl4, Zheng, Yi2, Xiaonan Han2,1Children's Hospital of Fudan University, Shanghai, Shanghai, China,2Cincinnati Children Hospital, Cincinnati, OH, USA,3Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, Beijing, China,4Ludwig Boltzmann Institute for Cancer Research, Vienna, Vienna, Austria
Objectives: CDC42 is a small GTPase that controls intestinal epithelial (IEC) apical-basal polarity, growth and intestinal epithelial stem cell (IESC) survival. However, the underlying mechanisms are not clear. Here, we determine the effects of CDC42 signaling upon intestinal epithelial stem cell (IESC) regenerative responses to intestinal injury.
Methods: Cdc42 floxed mice (Cdc42), Villin-Cre (VilCre) and Villin-CreER (VilCreER) mice were utilized to generate constitutive or inducible IEC-specific Cdc42 deficient mice. Lgr5-eGFP-IRES-CreER (Lgr5CreER) mice were used to determine the role of Cdc42 in Lgr5 IESCs. Irradiation, DSS challenge, and mouse intact crypt culture were used to evaluate the IESC regenerative activity of Cdc42-deficient IESCs.
Results: Coincident with mislocalization of lysozyme Paneth cells in the intestinal villus, depletion of Cdc42 in IECs led to reduced numbers of Lgr5 IESCs at the crypt base. VilCre;Cdc42 mice exhibited a disrupted villus crypt architecture, characterized by significantly increased crypt ¡°cyst¡ ± structure, intestinal villus hypertrophy and crypt fissions compared to littermate controls. These morphological aberrations in the small intestine, measured by villus height, villus width and crypt depth, were further progressed in the 4- and 6-month-aged mice compared to 1-month old Cdc42 depleted mice. To evaluate IESC regenerative activity, Cdc42 was inducibly deleted in VilCreER;Cdc42 mice, which were then exposed to either 12 Gy irradiation or 2.5% DSS administration. Loss of Cdc42 in IECs showed significantly reduced nascent crypts in small bowels following irradiation compared to controls (13.5 ± 0.5 versus 0.6 ± 0.1 crypts per mm, n 5, p < 0.01), and increased crypt loss in colon following DSS challenge. Intestinal crypts were isolated from VilCreER;Cdc42 or VilCre;Cdc4 mice, and cultured. Consistently, inducible depletion of Cdc42 in IECs resulted in markedly reduced enteroid crypt budding.
Conclusions: Cdc42 controls intestinal stem cell activity to maintain intestinal villus-crypt architecture. Loss of Cdc42 leads to increased sensitivity to intestinal mucosal injury.
270 DOES STANDARD THERAPY IN PAEDIATRIC CROHN'S DISEASE REALLY PREVENT OUR PATIENTS FROM THE NEED OF EARLY INITIATION OF ANTI-TNF TREATMENT?
Javier Martín-de-Carpi1, Patricia Domínguez-Sánchez1, Gemma Pujol-Muncunill1, Sergio Pinillos-Pisón1, Victor Vila-Miravet1, Melinda Moriczi2, Begoña Rodriguez-Azor2, Javier Blasco-Alonso2,3, María Juliana Serrano-Nieto2, Carlos Sierra-Salinas2,3, Víctor Manuel Navas-López2.3,1Unit for the Comprehensive Care of Paediatric Inflammatory Bowel Disease, Hospital Sant Joan de Déu, Barcelona, Spain, Pediatric Gastroenterology and Nutrition Unit, Hospital Materno Infantil, Málaga, Spain,3IBIMA, Biomedical Institute of Málaga, Spain
Background: Previous studies have shown the efficacy of exclusive enteral nutrition (EEN) for induction of remission in pediatric Crohn's disease (CD). The recent ECCO-ESPGHAN guidelines recommend the use of EEN (6–8 weeks) combined with early use of immunosuppressant as the optimal therapy in these patients at diagnosis. However, a high rate of relapse after EEN has been reported. Moreover, the potential effect of this strategy in postponing or avoiding the future need of biological treatment has not been evaluated. Our aim is to determine the proportion of CD patients diagnosed in the last years in our Centres and treated with EEN and thiopurines at diagnosis have required escalation to anti-TNF treatment during their follow-up.
Methods: Data from CD pediatric patients diagnosed between 2007 and 2014 who entered remission with EEN combined with thiopurines were retrospectively collected. The percentage of patients that needed to escalate to anti-TNF therapy (infliximab or adalimumab) after failure of maintenance treatment during their follow-up in our Unit was analysed. The follow-up period was considered until their last visit in our Unit at the time of preparing the abstract or up to the end of the transition programme to an adult IBD Unit.
Results: In total, 110 patients, 70 boys with a mean age at diagnosis 12.2 ± 2.9 years fulfilled the inclusion criteria. In 60 patients (54.9%) anti-TNF treatment was started; 24 received IFX and 36 ADA. The age of initiation of treatment with anti-TNF was 13.2 ± 2.3 years and the time from diagnosis of 10 months (IQR 4.5–20.5). We did not find any differences between both anti-TNF regimens in terms of age [IFX 13.7 (IQR 11.0–14.8) vs. ADA 13.5 (IQR 11.7–14.9), p = 0.718] or time from diagnosis [IFX 11.8 (IQR 4.0–20.0) vs. ADA 9.85 (IQR 4.6–24.5), p = 0.375]. Mean follow-up was 3.6 years (IQR 1.6–5.8).
Conclusion: The use of EEN has proved to be effective for the remission of pediatric CD and may delay somewhat the use of biological treatment. However, in our study 63% of the patients required initiation of anti-TNF treatment. Further studies showing the long-term follow-up of patients treated with standard therapy (EEN and immune-modulators) are needed to know the real effect of this combination in avoiding initiation of biological therapy.
271 PREDICTIVE FACTORS OF RESPONSE TO THE EXCLUSIVE ENTERAL NUTRITION IN NEWLY DIAGNOSED CROHN'S DISEASE CHILDREN
Víctor Manuel Navas-López, Melinda Moriczi, Begoña Rodriguez-Azor, Javier Blasco-Alonso, María Juliana Serrano-Nieto, Carlos Sierra-Salinas, Hospital Materno Infantil, Biomedical Institute of Málaga, Málaga, Spain
Background: Exclusive enteral nutrition (EEN) has been shown to be more effective than corticosteroids in achieving mucosal healing in children with Crohn's disease (CD) without having their side effects.
Objectives: The aims of this study were to determine the efficacy of EEN in terms of inducing clinical remission in newly diagnosed CD children; to study the efficacy of this therapeutic approach in improving the degree of intestinal mucosa inflammation and to describe the predictive factors of response to EEN.
Materials and Methods: An observational retrospective and prospective study including newly diagnosed CD patients who received at least 6 weeks of EEN. The degree of mucosal inflammation was assessed by fecal calprotectin (FC). Remission was defined as a wPCDAI < 12,5.
Results: Sixty-one patients (38 males) were included; the mean age at diagnosis was 11.5 ± 2.8 years. The median duration of EEN was 7.6 weeks (IQR 6.5–8.2). Fifty-two out of 58 patients who completed the EEN period (89.6% per-protocol analysis) achieved clinical remission. This percentage fell to 85% in the intention-to-treat analysis. The compliance rate was 95%. The FC levels (mcg/g) descended significantly at the end of EEN period: 665 IQR (503–836) vs. 177 IQR (125–342). As is shown in table 1, exclusive colonic CD (L2 of Paris classification), CRP and FC levels and disease activity were not predictive factors of response. Older patients and those with higher weight Z- score responded better to the EEN.
Conclusions: EEN administered for 6–8 weeks is effective for inducing clinical remission and achieving mucosal healing. The NEE must be used as the first therapeutic option in patients with CD independently of the age at diagnosis, the location of the disease and the value of wPCDAI.
272 LONG-TERM FUNCTIONAL OUTCOME OF PATIENTS WITH INFLAMMATORY BOWEL DISEASE DIAGNOSED DURING CHILDHOOD AND ADOLESCENCE
Wael El-Matary, Brenden Dufault, Stan P Moroz, Jeannine Schellenberg, Charles N Bernstein, University of Manitoba, Winnipeg, MB, Canada
Background: Inflammatory bowel disease (IBD) is a group of immune system disorders characterized by a chronic course with remissions and relapses. As with any chronic illness, IBD diagnosed early in life has a significant impact on physical, emotional and social development. Consequently, it is logical to speculate that patients with IBD may not do as well in education levels or employment status attained compared to their peers without IBD. The aim of this study was to assess the functional outcome of adult IBD patients followed in Manitoba whose diagnoses were initially made during childhood in comparison with an age and sex-matched population-based sample of healthy Canadians.
Methods: Adult patients who were initially diagnosed with IBD in childhood or adolescence (diagnosis was made < age of 18 years) and initially seen at the Pediatric Gastroenterology Clinic, the Children's Hospital, Winnipeg, Manitoba, Canada from January 1978 to December 2007 were invited to answer a semi-structured questionnaire regarding their highest level of educational achievement, employment and marital status. Each case was then age- and sex-matched with 5 random healthy adult Canadians from the Canadian Community Health Survey (CCHS 2012). Occupation was coded using Canadian National Occupation Classification (NOS 2011). Conditional binary logistic regression and random-effects ordinal logistic regression models were used for analysis.
Results: There were 397 patients with IBD seen (56% boys, 233 (59%) had Crohn's disease (CD), 141 (35%) had ulcerative colitis (UC), and 23 (6%) had unclassified IBD (IBD-U). The contact details were verified for 124 persons. Of the 124 approached, 12 persons were excluded as they either did not have IBD, had another chronic debilitating disease or did not complete the survey. A total of 112 (88%) completed the questionnaire, (mean age at diagnosis 12.9 years; range 4.3–17 years, 58 males, 76 with CD). The mean duration of follow-up was 14.3 years; range 3.1–34.5 years. Persons with IBD were more likely to earn more money per annum and attain a post-secondary school degree/diploma compared to those without IBD (odds ratio (OR) 1.72, 95% confidence interval (CI), 1.13 - 2.60, p < 0.01) (OR 2.73, 95% CI, 1.48 – 5.04, p < 0.01) respectively. There was no statistically significant difference between the 2 groups in employment or marital status (OR 0.96, 95% CI 0.58 – 1.58), OR 0.69, 95% CI, 0.44–1.06) respectively.
There was no significant difference between persons with CD compared to those with UC in all measured functional outcomes.
Conclusions: Adults with IBD diagnosed during childhood seem to achieve higher education levels compared to those without IBD. This would be enormously reassuring to children with IBD and their parents.
273 RAPID INFLIXIMAB INFUSION IN CHILDREN WITH INFLAMMATORY BOWEL DISEASE: A MUTLI-CENTER NORTH AMERICAN EXPERIENCE
Wael El-Matary1, Charles Samson2, Sabina Ali3, Andrew Grossman4,1University of Manitoba, Winnipeg, MB, Canada,2Washington University School of Medicine, St. Louis, MO, USA,3Stanford Children's Health, Walnut Creek, CA, USA,4on behalf of NASPGHAN IBD Committee, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Background: Infliximab (IFX) is a chimeric (part murine, part human) monoclonal antibody against tumor necrosis factor alpha (TNF-ą) used to treat inflammatory bowel disease (IBD). Typically IFX is administered via intravenous (IV) infusion over 2–3 hours. Since IFX is a protein-derived medication, infusions can lead to formation of anti-IFX antibodies (ATI) which may lead to infusion reactions (IRs) with subsequent infusions. IRs are reported in as many as 5% of infusions and to occur in 10–20% of patients.1,2 While the safety of rapid IFX infusion has been confirmed in several adult studies (1,2), it has been under-evaluated in children. Our aim was to examine the incidence of IRs associated with rapid infusion of IFX and report variation in pre-medication regimens among different centers and their effect on IRs.
Methods: The medical records of consecutive patients (< 21 years) with IBD who were on rapid IFX infusions between January 2014 and April 2016 from 3 North American centers were examined. Variables examined included patient demographics, diagnosis, duration of IFX treatment and duration of infusions, time interval between infusions, reported immediate and delayed infusion reactions, pre-medications for IFX, if any, and presence or absence of concomitant immunomodulators.
Results: A total of 53 patients (mean age 13.6+3.1 years, 29 males, 37 Crohn's disease, 15 ulcerative colitis, and 1 IBD-U) with 365 rapid infusions were included. All had at least the initial 3 induction infusions over 2–3 hours followed by rapid IFX infusions over 60 minutes for the maintenance infusions. The mean dose for IFX was 7 mg (range 4.9–13.8) /kg/infusion. Only 5 patients (9%) had IRs on rapid infusions. The incidence for immediate IRs was 0.03% and delayed IRs was 1%. None of these reactions resulted in discontinuation of IFX. Pre-medications included none (6 (11%) patients), acetaminophen (40 (75%) patients), anti-histamines (11 (20%) patients) and steroids (3 (5.5%) patients).∗. Thirty three (62%) patients were on concomitant immunomodulators. In a univariate logistic regression analysis, the presence of pre-medication, concomitant immunomodulators and IFX dose did not result in any significant effect on incidence of IRs.
Conclusions: Rapid IFX infusions over 60 minutes are safe and well-tolerated in children with IBD. This strategy may save significant time and health resources for both patients and healthcare providers. The presence of absence of pre-medications did not have any effect on the incidence of IRs. Larger prospective well-designed studies are needed to confirm our conclusions.
∗Several patients had more than one medication simultaneously.
References:1. Breyaert Cet al. Tolerability of shortened infusion times in patients with IBD: a single center cohort study. Am J Gastroenterol 2011;106:778; 2) Neef HC et al. Meta-analysis: rapid infliximab infusions are safe. Aliment Pharmacol Ther 2013;38:365.
NEUROGASTROENTEROLOGY & MOTILITY
284 PREDICTION OF INFANT COLIC SINCE THE DEFECATION PATTERN AND REGURGITATION: LOGISTIC REGRESSION MODEL
Alfredo Larrosa-Haro1, Laura E Flores-Gong2, Jesus Nares-Cisneros3, MC Rocio Macias-Rosales4, Carmen A Sanchez-Ramirez5, Mariana Gomez-Najera6, Heriberto Pinto-Aguilar7, David Rodriguez-Medina8,1Instituto de Nutrición Humana, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico,2Instituto Nacional de Pediatría, Ciudad de Mexico, Mexico,3Hospital de Especialidades # 71, Torreon, Coahuila, Mexico,4Hospital de Pediatria CMNO IMSS, Guadalajara, Jalisco, Mexico,5Universidad de Colima, Colima, Mexico,6Hospital de Regional de Alta Especialidad del Bajío, Leon, Guanajuato, Mexico,7Hospital San Javier, Guadalajara, Jalisco, Mexico,8Hospital de Gineco Obstetricia CMNO IMSS, Guadalajara, Jalisco, Mexico
Aim: Our aim was to develop a predictive model of infant colic since independent variables of the defecation pattern and the frequency of regurgitation.
Patient and methods: One-hundred and fifty consecutive infants attended by colic (Wessel criteria) at five GI outpatient clinics and 101 healthy infants seen for follow-up at two general pediatrics clinics were included. Cases with cow's milk allergy (exclusion/challenge trial), GERD (24-h esophageal pH test), and presence of enteropathogens in the stools (fresh smear and stool culture) were excluded. Independent variables included socio-demographic (parents age, education and employment; marital status; family size), type of diet, defecation pattern (times/day, days/week, stool consistency by Bristol classification, color and smell of feces) and associated GI symptoms (vomiting, abdominal distention, worsening during or after eating and hiccups). Statistics: chi square, OR, CI05% and binary regression models.
Results: The mean age was 11.7 (± 3.9) and 9 (± 7.6) weeks for controls and cases respectively (p
= 0.02); 48.9% were girls. Forty-three (16.8%) were exclusively breast fed; 49 (19.1%) received infant formula; and 164 (64.1%) mother's milk plus infant formula. The independent predictors of colic included in the final regression model were: stool frequency equal to or less than 5 per week (OR: 5.2, CI, 95%: 2.3–11.8); increased stool consistency (1–3 Bristol scale, OR: 3.4, CI, 95%: 1.5–7.5); regurgitation (OR:2.7, CI, 95%: 1.4–5); daily stool frequency equal to or less than 2 per day (OR: 2.3, CI, 95%: 1.1–4.5). Although the color and smell of feces had a significant association with colic, they were not included in the analysis due to their subjective nature. Socio-demographic variables and the type of feeding were not predictive of colic. Hiccups were more frequent in infants with colic but did not enter the model.
Conclusion: Our data point in the direction that defecation pattern plus regurgitation are predictors of colic once other causes of GI discomfort have been ruled out. Although a cross-sectional study does not evaluate causality, the association strength and de confident intervals suggest that in this series infant colic was associated to digestive disorders.
285 ABDOMINAL RADIOGRAPHS: APPROPRIATELY USED IN THE MANAGEMENT OF FUNCTIONAL CONSTIPATION IN CHILDREN?
Beate Beinvogl, Maireade McSweeney, Sabina Sabharwal, Samuel Nurko, Boston Children's Hospital, Boston, MA, USA
Abdominal radiographs (KUB) are frequently used to assess stool burden when managing pediatric constipation, despite evidence that radiographic findings poorly correlate with clinical symptoms or severity of fecal retention and despite recent guidelines which recommend obtaining KUBs only in children in whom fecal impaction is suspected but in whom physical examination is unreliable or not possible.
Aim: This study aims to discern reasons for obtaining KUBs and how they are used in diagnosis and management of pediatric constipation.
Method: 25 pediatric gastroenterologists were surveyed on 71 patients seen for known or suspected functional constipation and evaluation of which included obtaining a KUB. Physicians were given a questionnaire after the visit and asked about their reasons for obtaining a KUB. Plan, usefulness, utilization, and confidence in their plan before and after viewing the KUB. Multiple answers were permitted for each question. Confidence was rated on a scale from 1–5 (1 unsure, 5 very confident).
Results: Reasons for obtaining KUB:
Table 1: Plan of management before and after viewing KUB: 69% of physicians had a treatment plan in mind before obtaining KUB. After viewing the KUB, the plan to do a clean out at home was decreased by 11.2% of physicians, inpatient clean out by 1.4%. Adding an osmotic laxative was increased by 5.6%. No change in the plan whether to add a stimulant laxative. The plan not to make any changes was decreased by 5.7% after obtaining KUB. Decreasing laxatives increased by 2.8%. New plans after viewing KUB included administering an enema (2.8%) or suppository (2.8%). 47.6% implemented or changed their plan based on KUB findings.
Utilization of the KUB: 97.2% of physicians found KUB helpful for their visit. Stool burden on KUB was as expected (39.7%), worse (39.7%) or less (20.6%) than expected. 63.4% used both their personal and the radiologist read of the KUB, whereas 33.8% relied on the radiologist's read alone.
81.7% of physicians report that the KUB was helpful in making a diagnoses: Constipation as reason for abdominal pain (27%), Constipation (22%), demonstration to family (16%), fecal impaction (10%), worsening fecal retention (8.6%), stool retention as reason for incontinence (5%), need for inpatient disimpaction (2%).
Physician confidence: Mean level of confidence in management plan prior to obtaining abdominal radiograph was 2.41 ± 2.697 and increased at 4.07 ± 1.751 after viewing KUB.
Conclusion: KUBs are commonly obtained by pediatric gastroenterologists in managing functional constipation. Nearly all find it useful. Most common reason for obtaining a KUB was the assessment of stool burden and the need for a clean out, despite evidence that KUBs poorly correlate with clinical symptoms or severity of fecal retention, contradictory to current guidelines. This discrepancy highlights the need for further physician education.
286 SYMPTOM PRESENTATION AND CLINICAL OUTCOME IN CHILDREN WITH FUNCTIONAL DYSPEPSIA
Peace Dike, Bruno Chumpitazi, Eric H. Chiou, Antone Opekun, Robert J. Shulman, Baylor College of Medicine, Houston, TX, USA
Background: A subgroup of children with functional dyspepsia (FD) have gastroparesis (GP). It is unknown if either there are differences in symptoms (including both upper and lower gastrointestinal symptoms) or differences in clinical symptom resolution (outcome) between children with FD who have GP vs. those without GP.
Objective: To determine in children with FD whether the presence or absence of GP may affect either clinical symptoms or clinical symptom resolution (outcome).
Methods: Retrospective chart review of children with FD that completed a four-hour gastric emptying scintigraphy (GES) evaluation at a tertiary care children's hospital. Studies were completed between 2012–2013. Children were excluded if no symptoms were captured in the medical record; an organic etiology (e.g., celiac disease) was subsequently identified; or if they had previously had abdominal surgery. Patient demographics, GES results, symptoms (nausea, abdominal pain, vomiting, early satiety, weight loss/poor weight gain, fatigue, constipation, impairment in activities of daily living) at the time of first presentation and throughout their clinical course were systematically captured. The primary outcome was the severity of gastrointestinal symptoms at the time of the last identified follow-up visit (office visit or telephone encounter) in comparison to baseline. Outcomes were categorized as being: excellent (resolution of all symptoms); good (improvement in majority of symptoms with medication); fair (no improvement in majority symptoms); or poor (worsening in symptoms and/or impairment of activities of daily living). Statistical analyses (Chi-square or Fischer Exact) were completed using IBM SPSS Statistics 23 (Armonk, NY).
Results: 171 children with FD were included of whom 44 (25.7%) had GP. The mean (± SD) age at time of the GES was 12.5 ± 3.6 years and 117 (68.4%) were female. Overall, children with FD had the following symptoms: abdominal pain 141 (82.4%); nausea 75 (43.9%), vomiting 70 (40.9%), early satiety 31 (18.1%), weight loss/poor weight gain 50 (29.2%), fatigue 11 (6.4%), constipation 51 (29.8%), diarrhea 19 (11.1%), impaired activities of daily living (e.g., missing school) 32 (18.7%). Other than constipation (p < 0.05) (which was more common in those with GP), there were no differences in symptoms between those with GP and without GP. Outcomes: Children with GP did not differ from those without GP with respect to median [25%,75%] follow-up time (13.0 [5.5–32.0] vs. 7.4 [2.4–21.0] months, respectively). Clinical outcome was able to be determined in 139 (81.3%). Children with FD with GP had worse outcomes vs. those without GP (Table).
Conclusions: Constipation is the only differentiating symptom (more common) in those with FD with GP vs. without GP. Children with FD without GP had better clinical outcomes vs. those with GP.
287 SUGAR CONSUMPTION IN COLOMBIAN CHILDREN WITH FUNCTIONAL GASTROINTESTINAL DISORDERS
Carlos Velasco, Lina Valencia, Universidad del Valle, Cali, Valle, Colombia
Introduction: Hypothetically intake of certain foods can produce some types of functional gastrointestinal disorders (FGDs) in children. Objective: To determine the influence of sugar consumption in the occurrence of FGDs in children between 8–18 years of age from a public school in Cali, Colombia.
Methods: Cross-sectional study in children between 8 and 18 years old at a public school in Cali, Colombia. The outcome variable was measured by survey FGDs Rome III Criteria validated in Spanish. In the statistical analysis per occurrence ratio (95% CI) percentages, averages, standard deviations, 2x2 tables, ORs with their respective 95% CI were estimated. For statistical significance Fisher's exact test (p < 0.05) was used. To estimate the statistical model analysis of multiple logistic regression.
Results: Data 653 children were analyzed; the mean age was 13.19 years (between 8–18 years), the overweight prevalence was 28.9%. The FGDs prevalence was 19.9% and Functional Constipation (FC) was the most common disorder at 8.27%. There was notassociation or nutritional status influence in the occurrence of FGDs; however, those students who had excess sugar consumption (greater than 10% of total caloric value (TCV), had a four times greater opportunity to FGDs (95% CI, 2.04 to 7.68; p
= 0.00). The excess sugar consumption is a confounding factor in the study of the possible association between excess weight and FGDs
288 COULD THE ROME III CRITERIA PREVENT UNNECESSARY COLONOSCOPIES IN CHILDREN AND ADOLESCENTS ADMITTED FOR INVESTIGATION OF ABDOMINAL PAIN?
Claire Dupont-Lucas, Charlotte Grandjean-Blanchet, Bertrand Leduc, Christophe Faure, Colette Deslandres, Sainte Justine Hospital, Montreal, QC, Canada
Background: Based on Rome III criteria, functional gastrointestinal disorders (FGID) could only be diagnosed when organic disease had been excluded, resulting in some normal colonoscopies. The newly published Rome IV criteria advocate for a positive diagnosis of FGID based on appropriate medical evaluation, allowing the physician to make the diagnosis with “selective or no testing”. The objective of our study was to evaluate the diagnostic value of the Rome III criteria among pediatric patients undergoing colonoscopy for abdominal pain.
Methods: Between June 2013 and June 2015, all patients admitted for an elective colonoscopy in our pediatric endoscopy suite were invited to answer the qPGS questionnaire based on Rome III criteria for FGID in children/adolescents. Reason for colonoscopy, most recent complete blood count, result of colonoscopy and biopsies were obtained from the chart. Confirmed functional pain was defined as a normal colonoscopy and having Rome III criteria for « Irritable bowel syndrome », « Functional abdominal pain », « Functional abdominal pain syndrome », « Dyspepsia » or « Abdominal migraine ».
Results: Over the study period, 278 patients admitted for colonoscopy accepted to participate, 183 of which underwent colonoscopy primarily for abdominal pain. One hundred and three of these had a normal colonoscopy and 80 had abnormalities. There were 59% girls and median age was 14.8 years (IQR 25–75 11.4 – 16.3). Among the 103 patients with a normal colonoscopy, 85 (83%) fulfilled Rome III criteria, compared to 51 (64%) of the 80 patients who had an abnormal colonoscopy (p 0.01).
Predictors of normal colonoscopy among patients admitted for abdominal pain, by multivariable logistic regression, were: having Rome III criteria of functional pain (OR 2.9 [CI, 95% 1.15 – 7.32] p 0.02) and a higher mean corpuscular volume (OR 1.16 [CI, 95% 1.08 – 1.24], p < 0.0001). Normal colonoscopy was less likely if colonoscopy had also been ordered for intestinal bleeding (OR 0.25 [IC95% 0.1 – 0.62], p 0.003) or positive markers of inflammation (OR 0.31 [CI, 95% 0.10 – 0.90], p 0.03), and if neutrophils (OR 0.72 [CI, 95% 0.59 – 0.89], p 0.002) or monocytes (0.16 [CI, 95% 0.03 – 0.91], p 0.04) were increased.
The diagnostic properties of the QPGS alone to predict normal colonoscopy among patients admitted for abdominal pain without bleeding or inflammation, were: Sensitivity 86%, specificity 45%, positive predictive value 82% and negative predictive value 53%, Youden index 0.32.
Adding biological data, we built a score using parameters from the multivariable model: score -9.96 +0.53 x pain -0.69 x bleed – 0.59 x inflam – 0.32 x neutrophils – 1.85 monocytes +0.15 x MCV. Using this score to predict normal colonoscopy showed: Se 56%, Sp 79%, PPV 77%, NPV 58%, Youden index 0.35.
Conclusion: The Rome III criteria alone or associated with CBC were insufficient to predict normal colonoscopies among patients investigated for abdominal pain in a tertiary center.
289 DEGLUTITION DISORDERS IN CEREBRAL PALSY WITH INDICATION FOR GASTROTOSMY
Francisco de Agostinho Júnior1, Paula Cristina Cola1, Roberta Gonçalves da Silva2, Débora Afonso2, Cleber Gustavo R. Baldelin1,1Universidade de Marilia, Marilia, São Paulo, Brazil,2Universidade Estadual Paulista, Marilia, São Paulo, Brazil,
Introduction: Cerebral palsy refers to a group of disorders in the posture and motor control development, occurring as a result of a non-progressive lesion of the developing central nervous system. Deglutition disorders, oropharyngeal dysphagia, are a very common symptom in this population. The aim of this study was to describe the oral transit time of deglutition in cerebral palsy in individuals with indication for gastrostomy.
Materials and Methods: A cross-sectional clinical study, included 15 individuals with cerebral palsy and indication for gastrostomy, 10 males and 5 females, 13 with oral feeding and 2 with nasal probe, age range 1 until 14 years old, that were followed in two Research Dysphagia Centers in Brazil. The swallowing was analyzed by videofluoroscopic swallowing study. Normal oral transit time of deglutition until 3 seconds was considered normal. It was analyzed by 19 images from oral transit time of deglutition, by a specific software, using puree bolus (13 images) and liquid bolus (6 images).
Results: The middle and standard deviation for oral transit time of deglutition were 10.75 seconds (middle) and 11.76 (SD) to puree and 4.22 seconds (middle) and 1.54 (SD) to liquid.
Conclusions: These results demonstrated that oral transit time of deglutition in children with cerebral palsy with indication for gastrostomy is raised.
290 SOX2, PLP-1 EXPRESSING ENTERIC GLIA IN THE POSTNATAL GUT DIFFERENTIATE INTO NEURONS IN RESPONSE TO LPS
Jaime Belkind-Gerson1, Justin Reynolds1, Hannah Graham1, Ryo Hotta1, Nandor Nagy1, Lily S. Cheng1, Michal Kamionek2, Hai Ning Shi1, Allan M. Goldstein1,1Massachusetts General Hospital, Boston, MA, USA,2Carolinas Healthcare System, Charlotte, NC, USA
Objective: Mechanisms mediating adult enteric neurogenesis are largely unknown. Using models of inflammation-associated neurogenesis, and a strategic transgenic model approach we aimed to understand the cell-source.
Design: Dextran sodium sulfate (DSS) and Citrobacter rodentium colitis (CC) was induced in adult mice and colonic neurons were quantified. Sox2 GFP and PLP1 GFP mice served to confirm the glial specific expression of Sox2 and PLP1. Then Sox2CreER::YFP and PLP1creER::tdT mice were used for glial cell fate mapping after colitis. The effect of lipopolysaccharide (LPS) on enteric neurogenesis was tested in vitro and in vivo with or without administration of IAXO, a TLR4 inhibitor. Finally, expression of Sox2 as an indicator of neurogenesis was investigated in colonic neurons from human biopsies from patients with C. difficile or ulcerative colitis.
Results: Both DSS and CC led to an increase in colonic neuronal numbers. Following induction of colitis in adult Sox2CreER::YFP mice, YFP, initially expressed by enteric glia becomes expressed by neurons, without evidence of DNA replication suggesting glial cell transdifferentiation. A similar result was observed with the PLP1creER::tdT mouse. PLP1-expressing cells, which co-express S100b but not RET, also give rise to enteric neurons following colitis. These new neurons expressing YFP or tdT are, consistent with neurogenesis arising from glial transdifferentiation and less likely from neuronal progenitors. Systemic delivery of LPS into mice, led to an 18.4% increase in total neuronal density and a 40% increase in the number of double-immunoreactive Sox2+Hu+ neurons compared vehicle treated groups. The effect of LPS was abrogated by co-administration of IAXO. The percentage of Sox2-expressing enteric neurons in normal colon is 1–2% but rises up to 17% in human colitis.
Conclusions: These results suggest that colitis promotes enteric neurogenesis in adult mice and humans through transdifferentiation of Sox2 and PLP1 expressing enteric glia to neurons. This effect is mediated through microbiome-derived LPS via the TLR4 pathway. Further defining adult neurogenesis will improve our understanding of injury-associated dysmotility and identify targets for inducing therapeutic neurogenesis.
291 HEALTHCARE UTILIZATION ASSOCIATED WITH COMORBIDITIES IN CHILDREN WITH ANORECTAL MALFORMATIONS ACROSS THE USA
Karlo Kovacic, Sravan Matta, Katja Kovacic, Casey Calkins, Manu Sood, Medical College of Wisconsin, Milwaukee, WI, USA
Background: A variety of congenital anomalies are associated with anorectal malformations (ARMs) in children. Large population-based studies of the prevalence and healthcare utilization across different comorbidities associated with ARMs have not been performed in the U.S. Our aim was to identify trends in healthcare utilization differentiated by associated comorbidities in children with ARMs.
Method: We used Kids’ Inpatient Database (KID) for the years 2006, 2009 and 2012 for data collection. ICD 9 codes (48.40, 48.41, 48.42, 48.43, 48.49, 751.2, and 751.5) were used to identify patients with ARMs.
Results: A total of 2396 children <2 years of age were identified using weighted analysis from the KID database. Congenital anomalies other than ARM were reported in approximately 80% of patients. Hospital length of stay (LOS) and hospital charges were differentiated across multiple congenital anomalies (Table 1). Genetic disorders and Hirschsprung's disease as well as esophageal, heart, renal and vertebral anomalies were associated with significantly longer hospital stays and associated charges (length of stay > 11 days, charges > $100,000). In patients with VACTERL associations, the length of hospital stay and related charges were increasing proportionally with the number of VACTERL associations.
Conclusion: The vast majority of children with ARMs have one or more additional congenital anomaly. The management of these complex congenital anomalies is associated with a significant healthcare expenditure. The cost of healthcare management for ARMs is highly correlated with the types of associated comorbidities, in particular for patients with VACTERL syndrome. This data provides useful information for screening of associated anomalies, planning healthcare resource allocation and overall management of children with ARMs.