Management and monitoring of pediatric inflammatory bowel disease in the Asia-Pacific region: A position paper by the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition (APPSPGHAN) PIBD Working Group: Surgical management, disease monitoring, and special considerations.

Disease phenotype of pediatric inflammatory bowel disease (PIBD) in children from the Asia-Pacific region differs from that of children from the West. Many parts of Asia are endemic for tuberculosis, making diagnosis and management of pediatric Crohn's disease a challenge. Current available guidelines, mainly from Europe and North America, may not be completely applicable to clinicians caring for children with PIBD in Asia due to differences in disease characteristics and regional resource constraints. This position paper is an initiative from the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology and Nutrition (APPSPGHAN) that aims to provide an up-to-date, evidence-based approach to PIBD in the Asia-Pacific region. A group of pediatric gastroenterologists with a special interest in PIBD performed an extensive literature search covering epidemiology, disease characteristics and natural history, management, and monitoring. Attention was paid to publications from the region with special consideration to a resource-limited setting. This current position paper deals with surgical management, disease monitoring, immunization, bone health, and nutritional issues of PIBD in Asia. A special section on differentiating pediatric Crohn's disease from tuberculosis in children is included. This position paper provides a useful guide to clinicians in the surgical management, disease monitoring, and various health issues in children with IBD in Asia-Pacific region.

The Associations Between Preoperative Anthropometry and Postoperative Outcomes in Infants Undergoing Congenital Heart Surgery.

Aim: We explored the association between preoperative anthropometry and biochemistry, and postoperative outcomes in infants with CHD after cardiac surgery, as infants with congenital heart disease (CHD) often have feeding difficulties and malnutrition. Methodology: This was a retrospective review of infants (≤ 1-year-old) who underwent congenital heart surgery. Preoperative anthropometryin terms of preoperative weight-for-age z-score (WAZ), length-for-age z-score (LAZ), as well as preoperative serum albumin and hemoglobin concentrations, were evaluated against 6-month mortality, and morbidity outcomes including postoperative complications, vasoactive inotrope score, duration of mechanical ventilation, length of stay in the pediatric intensive care unit and in hospital, using the logistic regression or median regression models accounting for infant-level clustering. Results: One hundred and ninety-nine operations were performed in 167 infants. Mean gestational age at birth was 38.0 (SD 2.2) weeks (range 26 to 41 weeks). Thirty (18.0%) infants were born preterm (<37 weeks). The commonest acyanotic and cyanotic lesions were ventricular septal defect (26.3%, 44/167), and tetralogy of Fallot (13.8%, 23/167), respectively. Mean age at cardiac surgery was 94 (SD 95) days. Feeding difficulties, including increased work of breathing during feeding, diaphoresis, choking or coughing during feeding, and inability to complete feeds, was present in 54.3% (108/199) of infants prior to surgery, of which 21.6% (43/199) required tube feeding. The mean preoperative WAZ was-1.31 (SD 1.79). Logistic regression models showed that low preoperative WAZ was associated with increased risk of postoperative complications (odds ratio 1.82; p = 0.02), and 6-month mortality (odds ratio 2.38; p = 0.008) following CHD surgery. There was no meaningful association between the other preoperative variables and other outcomes. Conclusion: More than 50% of infants with CHD undergoing cardiac surgery within the first year of life have feeding difficulties, of which 22% require to be tube-fed. Low preoperative WAZ is associated with increased postoperative complications and 6-month mortality.

Pediatric Inflammatory Bowel Disease in Asia: Epidemiology and natural history.

Pediatric inflammatory bowel disease (PIBD) in Asia, once considered a rare entity, has seen a sharp increase in incidence over the preceding decade. However, there is a paucity of epidemiological data on PIBD in Asia, and the true disease burden is difficult to estimate due to the lack of national disease registries, prospective databases and the fact that much of existing published data are limited to single-center experiences. This sets the stage for examining recent published data on epidemiological trends and its natural history. Hence, we reviewed the relevant published literature on PIBD in order to summarize the epidemiological data in the Asian populations and compare it with the data available from the other population including Western population. Our review demonstrates that the rapid surge in PIBD incidence across Asian centers lies in contrast to the plateauing albeit high incidence rates in larger established Western cohorts. Important epidemiological trends observed across emerging Asian literature are the higher rates of perianal involvement at disease onset amongst pediatric Crohn's disease (CD) patients, a higher proportion of early-onset disease and the over-representation of the Indian ethnicity in multi-ethnic cohorts. A number of issues currently limit a robust comparison and hence the way forward would be to advocate the recognition of PIBD as an increasingly important public health problem with the need to establish robust disease registries.

Health-related quality of life, clinical outcomes, and subjective experiences of parent donors of pediatric liver transplant recipients.

PURPOSE: The understanding of the HRQOL issues for parent donors of children who underwent LDLT is lacking. We evaluated the HRQOL of donor and non-donor parents, described their subjective experiences and identified factors associated with lower HRQOL post-donation. METHODS: This is a cross-sectional study of parent donors whose children underwent LDLT, using SF-36v2 Health Survey to measure HRQOL, and a self-developed questionnaire to evaluate their subjective experiences. RESULTS: Of 32 pairs of donor and non-donor parents, 27 donor and 19 non-donor parents responded. The data of respondents were analyzed. Both donor and non-donor parents' SF-36v2 norm-based scores were average or above average as compared to the Singapore population. Donors who made lifestyle changes post-donation (adopting a healthy balanced diet, regular physical activity, quitting smoking, and moderate alcohol intake) were associated with lower GH (P = 0.009) and PF (P = 0.002) scores. Donors who took more than 3 months for full recovery had lower RP (P = 0.022) and BP scores (P = 0.038). On multivariate analysis, recipient complication of Clavien grade 3 or 4 was associated with increased RP score by 8.71 points (95% CI: 1.74-15.68), after adjusting for time taken for full recovery. Majority (88.8%) had self-reported recovery time under 6 months and returned to work within 3 months (74.0%). CONCLUSIONS: Donors with factors potentially associated with lower HRQOL may need more support to ensure better HRQOL outcomes post-donation.

Rapid rise in the incidence and clinical characteristics of pediatric inflammatory bowel disease in a South-East Asian cohort in Singapore, 1994-2015.

OBJECTIVES: Epidemiological studies on pediatric-onset inflammatory bowel disease (PIBD) are scarce in South-East Asia (SEA). This study aimed to evaluate the incidence trend and clinical characteristics of PIBD in a SEA cohort in Singapore over 22 years (1994-2015). METHODS: Case records of PIBD ≤18 years from the only two tertiary pediatric hospitals in Singapore were reviewed. The mean annual incidence (MAI) of PIBD was calculated based on Singapore's age-specific population data. RESULTS: Overall MAI of PIBD was 1.26 per 100 000 (95% confidence interval [CI] 0.56-1.96). During the first decade (1994-2004) MAI was 0.23 per 100 000 (95% CI 0.08-0.39); this rose almost 10-fold to 2.28 per 100 000 (95% CI 1.15-3.41) during the second decade (2005-2015). Linear regression analysis showed significant increase in MAI over the 22-year period (r = 0.826, P < 0001). Of the 228 patients, 61.0% had Crohn's disease (CD), 30.3% ulcerative colitis and 8.7% IBD-unclassified, with a mdian age at diagnosis of 10.47 years and a male predominance (58.3%); 37.7% of them aged <10 years at diagnosis and 17.5% were very early-onset IBD. In CD, 27.3% had stricturing and/or penetrating disease and 21.6% were with perianal disease. Indians had a disproportionately high representation while positive family history was rare (1.3%). CONCLUSIONS: Although PIBD is uncommon in Singapore, its incidence has risen dramatically over recent decades. A younger age of disease onset and higher proportions of perianal and stricturing/penetrating diseases suggest more aggressive disease than in Western data.

Eosinophilic oesophagitis in children: an uncommon occurrence in a predominantly Chinese population in Singapore.

INTRODUCTION: We aimed to determine the prevalence and clinical manifestations of eosinophilic oesophagitis (EoE) in children who presented to a tertiary care hospital in Singapore. METHODS: We conducted a retrospective review of all oesophageal biopsies taken during oesophagogastroduodenoscopy (OGD) from March 2010 to December 2011. The patients' demographics and clinical characteristics were collected. Biopsies were reviewed by a single pathologist who was blinded to the original reports, using the current consensus criteria for the histological diagnosis of EoE. RESULTS: Of the 88 children who had biopsies during OGD, 4 (4.5%) children (three boys, one girl; three Chinese, one Caucasian) were diagnosed with EoE. Their median age was 9.5 (range 4.0-12.0) years. The main clinical presentations were abdominal pain (in the three older children) and vomiting (in the youngest child). Three children had a history of atopy. Three children were diagnosed with EoE in the original histology reports, while one was diagnosed after the second review following histology demonstrating > 15 eosinophil granulocytes per high power field and microabscess formation. Endoscopy findings revealed oesophagitis in two children, one of whom was already on acid suppression therapy. Although three children were started on acid suppression therapy, they continued to be symptomatic. One child was also treated with swallowed fluticasone and two with food allergen avoidance, resulting in symptom improvement. CONCLUSION: Although EoE is uncommon in Singapore, greater awareness is needed among family physicians and general paediatricians. Paediatric gastroenterologists should alert pathologists when sending biopsy specimens that are suspicious for EoE.

Serum hepatocyte growth factor and vascular endothelial growth factor in children with acute liver failure.

OBJECTIVES: Hepatocyte growth factor (HGF), a potent mitogen, and vascular endothelial growth factor (VEGF), a potent angiogenic factor, may play roles in hepatocyte regeneration in patients with acute liver failure (ALF). The aim of this study was to investigate serum levels of HGF and VEGF in children with ALF. PATIENTS AND METHODS: Serum samples were collected on admission from 25 children with ALF (median age, 11.1 y; range, 1.3-17.1 y; 11 male, 14 female) and 12 normal children (9.1 y; range, 5.4-15.4 y; 6 male, 6 female). Aetiology of ALF was 13 non-A to E hepatitis, 3 viral, 3 toxic, and 6 other. HGF and VEGF in sera were assayed by enzyme-linked immunosorbent assay. RESULTS: Median HGF levels in patients (10,157 pg/mL; range, 3412-73,420 pg/mL) were significantly higher than in controls (855 pg/mL, 510-1253 pg/mL; P < 0.001). Median VEGF levels in patients (164 pg/mL, 0-1588 pg/mL) were not significantly different from those in controls (214 pg/mL, 11-527 pg/mL). There was no relationship of HGF or VEGF levels to the aetiology of liver failure. There was a positive correlation between serum HGF and international normalized ratio (r = 0.73, P < 0.001), but not with levels of serum aspartate aminotransferase, bilirubin, or VEGF. There was no correlation between VEGF levels and international normalized ratio, aspartate aminotransferase or bilirubin. CONCLUSIONS: Serum levels of HGF but not VEGF are increased in children with acute liver failure.

Transplant immunology.

The immune response to an allogeneic transplanted organ is T-cell dependent. It is governed partially by the context in which the T-cell encounters the antigen and can range from apoptosis, anergy, and neglect to full activation. The current armamentarium of immunosuppressive agents acts to inhibit the various steps of this T-cell activation pathway; at the level of the T-cell receptor (monoclonal antibodies such as OKT3), intracellular signally (calcineurine-inhibitors), DNA synthesis (azathioprine), or to cause lymphocyte depletion (ATG, ALG). Most protocols use a combination of agents for induction and maintenance immunosuppression. Although successful in preventing and treating allograft rejection, they are not without side effects. With improved patient and graft survival rates, adverse events such as hypertension, nephrotoxicity, hyperglycaemia, and lymphoproliferative disease become increasingly important issues. Newer drugs (IL-2 receptor antagonists, mycophenolate mofetil, rapamycin) have been introduced in an attempt to spare or avoid these adverse effects. Inducing graft tolerance and long-term drug-free survival is the goal of transplant immunologists. Postulated mechanisms include clonal deletion, anergy, and immunoredirection. Although a number of methods have been tested experimentally, none has been proven to induce tolerance for routine clinical use. Immunosuppression remains the cornerstone of the success of organ transplantation. Until investigators are able to induce tolerance in their transplant recipients or develop a tolerance assay, they would need to continue to tailor their immunosuppressive therapy according to the risk profile of the individual recipient.

Mycophenolic acid and mycophenolic acid glucuronide pharmacokinetics in pediatric liver transplant recipients: effect of cyclosporine and tacrolimus comedication.

Determinants of the wide interindividual variability of the pharmacokinetics of mycophenolic acid (MPA) in 21 stable pediatric liver transplant recipients were investigated in relation to the kinetics of the drug's major phenolic glucuronide metabolite (MPAG), cyclosporin (CsA), or tacrolimus (Tac) co-medication and liver and renal function. Trough concentrations (C(0) ) most reliably predicted the area under the curve (AUC) of 0-7 hours MPA plasma concentrations (r (2) = 0.650). Co-medication with CsA demanded higher MPA mofetil (MMF) doses to achieve equivalent trough levels than Tac (362 vs. 178 mg per mg/L, P= 0.004). Median MPA C(0) (range) was significantly lower during CsA co-therapy when corrected for MMF dose (2.8 vs. 5.6 mg MPA/L for Tac, P= 0.006). The AUC of MPAG was correspondingly higher during CsA co-medication (229 vs. 94 mg/L/h for Tac, P = 0.012) with the MPA-to-MPAG ratio at C(0) correspondingly lower (0.10 vs. 0.14, respectively, P = 0.04). This suggested contrasting effects of CsA and Tac on MPA glucuronidation or its excretion and enterohepatic recirculation. MPAG AUC was correlated to body weight and creatinine clearance. Children with elevated aspartate transaminase (AST; but with no evidence of rejection on liver biopsy, n = 7) had significantly lower MPA trough levels compared with those in whom AST was normal (0. 77 vs. 1.76 mg/L, P = 0.05), but there was no difference in the MMF dose per body weight. Examination of the MPA profiles in these subjects showed significantly lower MPA concentrations from 120 minutes after dose until the end of the 7-hour profile and suggest an accelerated clearance or decreased enterohepatic recirculation.)