Venous Thromboembolic Complications in Pediatric Gastrointestinal Diseases: Inflammatory Bowel Disease and Intestinal Failure

In children with gastrointestinal disorders such as inflammatory bowel disease (IBD) and intestinal failure (IF), the risk of venous thromboembolism (VTE) is increased. VTE may lead to pulmonary embolism, sepsis and central line infection, stroke and post-thrombotic syndrome. The purpose of this review is to summarize current knowledge and recent advances around VTE management in pediatric gastroenterology with a focus on IBD and IF. The VTE incidence in children with IBD is reported to be around 4–30 per 10,000 patient-years, with higher incidences for hospitalized children. While in general, IF is less common than IBD, the VTE incidence in children with IF is around 750 per 10,000 patient-years. The most common risk factors for development of VTE involve deviations leading to Virchow's triad (endothelial damage, stasis, and hypercoagulability) and include active inflammation, particularly with colonic involvement, presence of a central venous catheter, underlying thrombophilia, reduced mobility, surgery, and hospitalization. Classes of anticoagulants used for treatment of VTE are low molecular weight heparins and vitamin K antagonists. However, the use of direct oral anticoagulants for treatment or prevention of VTE has not been studied in this pediatric population yet. Pediatric gastroenterologists apply different VTE prevention and treatment strategies due to lack of literature and lack of consensus. We discuss the role of primary and secondary prophylactic use of anticoagulants, and provide tools and recommendations for screening, prevention and management for the specific pediatric populations

Developmental changes in the processes governing oral drug absorption

Pharmacotherapy in children often consists of oral medication. Effectiveness of oral prescriptions may be infl uenced by extrinsic (formulation, nutrition, and co-medication) and intrinsic factors (physiological and diseaserelated variation). During development the GI characteristics change: swallowing refl exes, excretion of digestive enzymes, intestinal motility, transit time and intestinal transporters and drug metabolizing enzymes. For example, changes in drug effl ux transporters result in a decrease or increase in expelling drugs back into the intestinal lumen and thereby in variation in oral bioavailability. Closing the main information gaps on the ontogeny of GI processes governing oral drug absorption would allow for more accurate prediction of the oral disposition of drugs in children of all ages. Different ex- and in vitro study designs, as drug dissolution/solubility tests, in vitro drug metabolism and transporter studies and in vivo drug-microdosing can be used to elucidate the age-related changes in GI processes to better understand oral drug disposition in children. Using these data in PB-PK models may further guide individualized pediatric drug therapy.</p

Gut microbiota and its diet-related activity in children with intestinal failure receiving long-term parenteral nutrition

Background: This study characterized gut microbiota and its diet-related activity in children with intestinal failure (IF) receiving parenteral nutrition (PN) compared with those of healthy controls (HC) and in relation to disease characteristics. Methods: The fecal microbiota and short-chain fatty acids (SCFAs) were measured in 15 IF patients (n = 68) and 25 HC (n = 25). Results: Patients with IF had a lower bacterial load (P =.003), diversity (P <.001), evenness (P <.001) and richness (P = 0.006) than HC. Patients with surgical IF had lower diversity (P <.039) than those with functional IF. Propionic acid and butyric acid (p <.001) were lower and d-lactate and l-lactate were higher (p < 0.001) in IF patients than in HC. The energy supplied by PN (%PN) was negatively associated with microbiota diversity and SCFA profile. IF patients had more Escherichia-Shigella (P =.006), Cronobacter (P =.001), and Staphylococcus (Operational Taxonomic Unit 14, P <.001) and less Faecalibacterium (P < 0.001) and Ruminococcus 1 and 2 (P <.001). Duration of PN (P =.005), %PN (P =.005), and fiber intake (P =.011) were predictive of microbiota structure. Higher intake of enteral nutrition was associated with microbiota structure and function closer to those of HC. Conclusions: Microbiota composition and its diet-related function are altered in IF, with depletion of beneficial SCFAs and species and supraphysiological increase of potentially harmful pathobionts. The influence of this compositional and functional microbial dysbiosis on patients’ outcomes and management warrants further exploration

Ontogeny of human hepatic and intestinal transporter gene expression during childhood: Age matters

Many drugs prescribed to children are drug transporter substrates. Drug transporters are membrane-bound proteins that mediate the cellular uptake or efflux of drugs and are important to drug absorption and elimination. Very limited data are available on the effect of age on transporter expression. Our study assessed age-related gene expression of hepatic and intestinal drug transporters. Multidrug resistance protein 2 (MRP2), organic anion transporting polypeptide 1B1 (OATP1B1), and OATP1B3 expression was determined in postmortem liver samples (fetal n = 6, neonatal n = 19, infant n = 7, child n = 2, adult n = 11) and multidrug resistance 1 (MDR1) expression in 61 pediatric liver samples. Intestinal expression of MDR1, MRP2, and OATP2B1 was determined in surgical small bowel samples (neonates n = 15, infants n = 3, adults n = 14). Using real-time reverse-transcription polymerase chain reaction, we measured fetal and pediatric gene expression relative to 18S rRNA (liver) and villin (intestines), and we compared it with adults using the 22 -Delta;Delta;Ct method. Hepatic expression of MRP2, OATP1B1, and OATP1B3 in all pediatric age groups was significantly lower than in adults. Hepatic MDR1 mRNA expression in fetuses, neonates, and infants was significantly lower than in adults. Neonatal intestinal expressions of MDR1 and MRP2 were comparable to those in adults. Intestinal OATP2B1 expression in neonates was significantly higher than in adults. We provide new data that show organ- and transporter-dependent differences in hepatic and intestinal drug transporter expression in an age-dependent fashion. This suggests that substrate drug absorption mediated by these transporters may be subject to age-related variation in a transporter dependent pattern. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics

Cognitive Outcomes in Children with Conditions Affecting the Small Intestine: A Systematic Review and Meta-analysis

Objectives:The aim of the study was to assess cognitive outcomes in children with intestinal failure (IF) and children at high risk of IF with conditions affecting the small intestine requiring parenteral nutrition.Methods:EMBASE, Cochrane, Web of Science, Google Scholar, MEDLINE, and PsycINFO were searched from inception to October 2020. Studies were included constituting original data on developmental quotient (DQ), intelligence quotient (IQ) and/or severe developmental delay/disability (SDD) rates assessed with standardized tests. We used appropriate standardized tools to extract data and assess study quality. We performed random effects meta-analyses to estimate pooled means of DQ/IQ and pooled SDD rates (general population mean for DQ/IQ: 100, for percentage with SDD: 1.8%) for 4 groups: IF, surgical necrotizing enterocolitis (NEC), abdominal wall defects (AWD), and midgut malformations (MM). Associations of patient characteristics with DQ/IQ were evaluated with meta-regressions.Results:Thirty studies met the inclusion criteria. The pooled mean DQ/IQ for IF, NEC, AWD, and MM were 86.8, 83.3, 96.6, and 99.5, respectively. The pooled SDD rates for IF, NEC, AWD and MM were 28.6%, 32.8%, 8.5%, and 3.7%, respectively. Meta-regressions indicated that lower gestational age, longer hospital stay, and higher number of surgeries but not parenteral nutrition duration, were associated with lower DQ/IQ.Conclusions:Adverse developmental outcomes are common in children with IF and NEC, and to a much lesser extent in children with AWD and MM. It is important to monitor cognitive development in children with conditions affecting the small intestine and to explore avenues for prevention and remediation

Gut microbiota and its diet-related activity in children with intestinal failure on long-term parenteral nutrition

Background: This study characterized the gut microbiota and its diet‐related metabolic activity in children with intestinal failure (IF) on parenteral nutrition (PN) compared with healthy controls and in relation to disease characteristics. Methods: Serial fecal samples were collected from 15 IF patients (n = 68) and from 25 healthy children (n = 25). The fecal microbiota, and short chain fatty acids (SCFA) were measured. Results: The microbiota of patients with IF had a lower bacterial load (p = 0.003), Shannon diversity index (p&lt;0.001), taxon evenness (p&lt;0.001) and richness (p = 0.006) than healthy controls. Patients with surgical IF had lower α‐diversity (p&lt;0.039) than those with functional IF. Patients with IF had less propionic and butyric acid (p&lt;0.001), and more D and L‐lactate than healthy controls (p&lt;0.001). The percentage of calories supplied by PN (%PN) was negatively associated with microbiota diversity and influenced SCFA profile. IF patients had more Escherichia‐Shigella (p = 0.006), Cronobacter (p = 0.001) and Staphylococcus (OTU 14, p&lt;0.001) and less Faecalibacterium (p&lt;0.001) and Ruminococcus 1 and 2 (p&lt;0.001). Duration of PN (R2 = 6%, p = 0.005), % of calories from PN (R2 = 6%, p = 0.005) and fiber intake (R2 = 5%, p = 0.011) were predictive of microbiota community structure. A higher intake of enteral nutrition was associated with a microbiota composition and function closer to that of the healthy status. Conclusions: The microbiota composition and its diet‐related function are altered in pediatric IF, with profound depletion of beneficial SCFA and species, and supraphysiological increase of potentially harmful pathobionts. The influence of this compositional and functional microbial dysbiosis on patients’ clinical outcomes and management warrants further exploration

Gut microbiota and its diet‐related activity in children with intestinal failure on long‐term parenteral nutrition

Background: This study characterized the gut microbiota and its diet‐related metabolic activity in children with intestinal failure (IF) on parenteral nutrition (PN) compared with healthy controls and in relation to disease characteristics. Methods: Serial fecal samples were collected from 15 IF patients (n = 68) and from 25 healthy children (n = 25). The fecal microbiota, and short chain fatty acids (SCFA) were measured. Results: The microbiota of patients with IF had a lower bacterial load (p = 0.003), Shannon diversity index (p&lt;0.001), taxon evenness (p&lt;0.001) and richness (p = 0.006) than healthy controls. Patients with surgical IF had lower α‐diversity (p&lt;0.039) than those with functional IF. Patients with IF had less propionic and butyric acid (p&lt;0.001), and more D and L‐lactate than healthy controls (p&lt;0.001). The percentage of calories supplied by PN (%PN) was negatively associated with microbiota diversity and influenced SCFA profile. IF patients had more Escherichia‐Shigella (p = 0.006), Cronobacter (p = 0.001) and Staphylococcus (OTU 14, p&lt;0.001) and less Faecalibacterium (p&lt;0.001) and Ruminococcus 1 and 2 (p&lt;0.001). Duration of PN (R2 = 6%, p = 0.005), % of calories from PN (R2 = 6%, p = 0.005) and fiber intake (R2 = 5%, p = 0.011) were predictive of microbiota community structure. A higher intake of enteral nutrition was associated with a microbiota composition and function closer to that of the healthy status. Conclusions: The microbiota composition and its diet‐related function are altered in pediatric IF, with profound depletion of beneficial SCFA and species, and supraphysiological increase of potentially harmful pathobionts. The influence of this compositional and functional microbial dysbiosis on patients’ clinical outcomes and management warrants further exploration

Long-term evaluation of faecal calprotectin levels in a European cohort of children with cystic fibrosis

Objective: Intestinal inflammation with contradictory data on faecal calprotectin (fCP) levels is documented in patients with cystic fibrosis (CF). The aim of this study was to longitudinally evaluate fCP in a cohort of children with CF and their relationship with clinical variables. Design: Prospective observational study to assess evolution of fCP levels, primary aimed at improving fat absorption. Along 1.5 years of follow-up (November 2016-May 2018) with four study visits pertaining to a pilot study (two of four) and to a clinical trial (two of four), the study outcomes were measured. Setting: Six European CF centres in the context of MyCyFAPP Project. Subjects: Children with CF and pancreatic insufficiency (2-18 years old). Main outcome measurements: fCP levels, pulmonary function (percentage of forced expiratory volume in 1 s (FEV1%)) and coefficient of fat absorption (CFA). Additionally, in the last two visits, gastrointestinal (GI) symptoms were evaluated through the PedsQL-GI Questionnaire. Linear mixed regression models were applied to assess association between fCP and FEV1, CFA and GI symptoms. Results: Twenty-nine children with CF and pancreatic insufficiency were included. fCP levels were inversely associated with total modified specific PedsQL-GI score (p=0.04) and positively associated with diarrhoea (p=0.03), but not with CFA. Along the four study visits, fCP significantly increased (from 62 to 256 μg/g) and pulmonary function decreased (from 97% to 87%), with a significant inverse association between the two study outcomes (p&lt;0.001). Conclusions: In children with CF, fCP levels are inversely associated with pulmonary function and thus the specificity of fCP as a marker of intestinal inflammation in paediatric patients with CF warrants further investigation.</p

Long-term evaluation of faecal calprotectin levels in a European cohort of children with cystic fibrosis

Objective: Intestinal inflammation with contradictory data on faecal calprotectin (fCP) levels is documented in patients with cystic fibrosis (CF). The aim of this study was to longitudinally evaluate fCP in a cohort of children with CF and their relationship with clinical variables. Design: Prospective observational study to assess evolution of fCP levels, primary aimed at improving fat absorption. Along 1.5 years of follow-up (November 2016-May 2018) with four study visits pertaining to a pilot study (two of four) and to a clinical trial (two of four), the study outcomes were measured. Setting: Six European CF centres in the context of MyCyFAPP Project. Subjects: Children with CF and pancreatic insufficiency (2-18 years old). Main outcome measurements: fCP levels, pulmonary function (percentage of forced expiratory volume in 1 s (FEV1%)) and coefficient of fat absorption (CFA). Additionally, in the last two visits, gastrointestinal (GI) symptoms were evaluated through the PedsQL-GI Questionnaire. Linear mixed regression models were applied to assess association between fCP and FEV1, CFA and GI symptoms. Results: Twenty-nine children with CF and pancreatic insufficiency were included. fCP levels were inversely associated with total modified specific PedsQL-GI score (p=0.04) and positively associated with diarrhoea (p=0.03), but not with CFA. Along the four study visits, fCP significantly increased (from 62 to 256 μg/g) and pulmonary function decreased (from 97% to 87%), with a significant inverse association between the two study outcomes (p&lt;0.001). Conclusions: In children with CF, fCP levels are inversely associated with pulmonary function and thus the specificity of fCP as a marker of intestinal inflammation in paediatric patients with CF warrants further investigation.</p

Children with Intestinal Failure are at Risk for Psychopathology and Trauma

Objectives: The objective of this study is to assess the psychopathology and medical traumatic stress in children with intestinal failure (IF) and identify associated risk factors. Methods: Two-center study, performed from September 2019 until April 2022 (partly during COVID-19 pandemic), including children (1.5-17 years) with IF, dependent on parenteral nutrition (PN) or weaned off PN, treated by a multidisciplinary IF-team. Psychopathology in children was evaluated with a semi-structured interview assessing psychiatric classifications and validated questionnaires assessing emotional (internalizing) and behavioral (externalizing) problems. Medical traumatic stress was assessed with a validated questionnaire. Problem scores were compared with normative data. Associations between clinical characteristics and outcomes were analyzed with linear regression analyses. Results: Forty-one (of 111 eligible) children were included [median age 8.9 years (interquartile range, IQR 5.5-11.8), 54% female, 73% born preterm]. Median PN-duration was 17.3 months (IQR 6.9-54.0); 17 children (41%) were still PN-dependent. One third of the children met criteria for at least 1 psychiatric classification (compared with 14% in age-matched general population). Anxiety disorders and attention deficit hyperactivity disorder were most common. In school-aged children (n = 29, 6-17 years), significantly increased emotional problems were consistently reported by children (P = 0.011), parents (P &lt; 0.001), and teachers (P = 0.004). In preschool children (n = 12, 1.5-5 years), no significant differences with normative data were found. Subclinical or clinical emotional problems were reported in 19 children (46%). Medical traumatic stress was present in 14%, and 22% of children had received psychological help for trauma before. Lower gastrointestinal related quality of life was associated with more emotional problems, but not PN-duration. Conclusions: Children with IF, particularly school-aged children, are at risk for psychological problems which is reflected by the high rate of received psychotherapy and the high rate of emotional problems and psychiatric classifications.</p