Recent developments in the assessment and management of inflammatory bowel disease in childhood: a narrative review.

Background and Objective: The landscape of paediatric inflammatory bowel disease (pIBD) continues to evolve in an era of increasing incidence. There have been rapid developments in understanding, as we begin to perceive IBD as a spectrum of conditions, alongside advancements in monitoring and treatment. The objective of this article was to provide an overview of recent advances and challenges in the management of pIBD, with a focus on sustainable healthcare, personalised therapy, genomics, new drugs and avenues for future optimisation. Methods: We present a narrative review that synthesises and summarises recent research (2017-2022) related to pIBD. We undertook a structured search of the literature (PubMed and Medline) and additional articles were identified through manual searches of reference lists. Evidence tables were compiled for disease outcomes. Key Content and Findings: In this review we outline current practice, integrating clinical guidelines and contemporary research. We discuss initial investigations (including suggested threshold for paediatric faecal calprotectin), specialist investigations for disease monitoring [with reference to video capsule endoscopy (VCE) and therapeutic drug levels] and outline new and established treatment options. Biomarkers and genomic testing are examined as important tools for individualising care and identifying potential therapeutic targets, including for top-down therapy. Despite these advances, significant challenges remain, including the need for further research to understand the mechanisms of disease and the translation of these advances into real-world improvements in practice. Conclusions: Recent advances in understanding of the pathogenesis of pIBD, alongside genomic and pharmacological developments have added more tools to the armamentarium for the treatment of these conditions and highlighted ongoing areas of research need.

Longitudinal pilot study of oxygen saturation indices in healthy preterm infants.

BACKGROUND: This study aimed to determine patterns of nocturnal pulse oximetry indices in moderate to late preterm infants, and investigate the relationship between oxygen desaturations, the apnoea hypopnoea index, and both corrected gestational and postnatal age. METHODS: 21 healthy infants born at 32 + 0 - 36 + 6 weeks gestation underwent serial nocturnal pulse oximetry studies and respiratory polygraphy studies until 40 weeks corrected gestational age (CGA). The main outcome measures were number of >3% oxygen desaturations/hour (ODI3), mean oxygen saturations, and number of apnoeas and hypopnoeas/hour. RESULTS: Median ODI3 increased between weeks 1 and 3 from 49.9 to 85.4/hour (p = 0.017). Mean oxygen saturations reached a corresponding nadir of 96.0% in week 3, then increased to 96.8% in week 6 (p = 0.019). Mixed effects modelling demonstrated that ODI3 and mean saturations were influenced by postnatal age but not CGA (p < 0.05). Desaturations frequently occurred without an apnoea or hypopnoea. CONCLUSION: ODI3 rises then falls during the first 8 weeks of life in moderate to late preterm infants, independently of CGA. These interesting preliminary results highlight the importance of further serial data collection to generate age-specific normal ranges, and develop a better understanding of respiratory control in preterm infants. IMPACT: The frequency of >3% oxygen desaturations (ODI3) in healthy moderate to late preterm infants rises then falls after birth, peaking in postnatal week 3. There is a corresponding nadir in mean saturations. There were significant non-linear relationships between ODI3/mean saturations and postnatal age, but not corrected gestational age. The majority of brief oxygen desaturations occurred without an apnoea or hypopnoea. Normal ranges for oxygen saturation indices are not known in this population. These results demonstrate the need for further serial data collection to generate age-specific normal ranges and inform oxygen prescribing guidelines.

A Scoping Review: Urinary Markers of Metabolic Maturation in Preterm Infants and Future Interventions to Improve Growth.

Background: Growth failure in infants born preterm is a significant issue, increasing the risk of poorer neurodevelopmental outcomes and metabolic syndrome later in life. During the first 1000 days of life biological systems mature rapidly involving developmental programming, cellular senescence, and metabolic maturation, regulating normal growth and development. However, little is known about metabolic maturation in infants born preterm and the relationship with growth. Objective: To examine the available evidence on urinary markers of metabolic maturation and their relationship with growth in infants born preterm. Eligibility criteria: Studies including in this scoping review using qualitative or quantitative methods to describe urinary markers of metabolic maturation and the relationship with growth in infants born preterm. Results: After a screening process 15 titles were included in this review, from 1998-2021 drawing from China (n = 1), Italy (n = 3), Germany (n = 3), Greece (n = 1), Japan (n = 2), Norway (n = 1), Portugal (n = 1), Spain (n = 2) and USA (n = 1). The included studies examined urinary metabolites in 1131 infants. A content analysis identified 4 overarching themes relating to; (i) metabolic maturation relative to gestational age, (ii) metabolic signature and changes in urinary metabolites over time, (iii) nutrition and (iv) growth. Conclusion: The results of this scoping review suggest there are considerable gaps in our knowledge relating to factors associated with metabolic instability, what constitutes normal maturation of preterm infants, and how the development of reference phenome age z scores for metabolites of interest could improve nutritional and growth outcomes.

Time to normalisation of tissue transglutaminase in paediatric coeliac disease is dependent on initial titre and half of patients will normalise within 12 months.

BACKGROUND: Coeliac disease (CD) is common. Response to a gluten-free diet is assessed through serial measurement of tissue transglutaminase (TTG) antibody titre. However, the relationship of TTG titres to symptoms and the speed of normalisation is poorly understood. METHODS: Patients seen in 2020, and under follow-up in the Southampton CD clinic, had blood results, growth measures and symptom data collated. Time to normalisation, predictors of normalisation and relationship of TTG to growth/symptoms were assessed. RESULTS: 57 patients were included. All had TTG results from the time of diagnosis and follow-up. All families reported dietary compliance.Median TTG at diagnosis was 100 µ/L (range 0.3-4360), 94.7% of the patients had symptoms compatible with CD. At 6-12 months after diagnosis, the median TTG was 3.8 µ/mL (range 0.3-133). In terms of response, 29 of the 57 patients (50.9%) had a TTG below 4 µ/mL (upper normal limit). A further 25 patients (43.9%) had a TTG<10 times the upper limit of normal. Ten patients (17.5%) had a persistently high TTG (median=8.55 µ/mL, range 4.1-303) after >12 months.TTG at diagnosis was correlated with TTG at 6-12 months, ß=0.542, p=0.000016. Patients with TTG<10 times the upper limit of normal at diagnosis group were more likely to have normalised at 6-12 months compared with >10 times normal (85% vs 32.4%, p=0.0015). TTG titres did not correlate with growth measures (Z-scores) at diagnosis or at follow-up. CONCLUSIONS: Normalisation of TTG levels occurs within 6-12 months for around half of patients. Higher TTG levels at diagnosis take longer to normalise. The role of compliance is unclear.

The impact of national lockdown on nutritional status of children with inflammatory bowel disease.

BACKGROUND: The COVID-19 pandemic has had wide-reaching primary and secondary health implications. The UK government implemented a national lockdown to slow the rate of infection at the end of March 2020, lasting until early summer 2020. The results from a UK nationwide survey suggest the majority of inflammatory bowel disease patients were followed up using technology-enabled care services (TECS) during this time. We therefore aimed to explore the impact of the pandemic on nutritional status of children with inflammatory bowel disease, focusing on the effect of national lockdown from March to early summer 2020. METHODS: A retrospective study was conducted. All patients with a diagnosis of inflammatory bowel disease, aged <18 years, and under the care of Southampton Children's Hospital were eligible for inclusion. Those patients who attended an outpatient appointment during time period 1 (November 2019 to February 2020), and following the period of national lockdown, time period 2 (July to November 2020), were included in the analysis. RESULTS: In total, 116 patients had paired measures. Using the World Health Organization criteria of nutritional status, 19% (n = 22/116) were mildly malnourished with a body mass index Z score (BMIZ) < -1. In this group, the mean BMIZ was -1.3 ± 0.9 at time point 1 versus -1.9 ± 0.9 at time point 2 (p = 0.03). The mean BMIZ score of those children who were overweight at time point 1 was 1.2 ± 1.2 versus 1.6 ± 1.4 at time point 2 (p = 0.2) During the period of lockdown, 27% of malnourished children (n = 6/22), 2% of normally nourished children (BMIZ > -1 to < 1) (n = 1/51) (p ≤ 0.0001) and none of the overweight children (BMIZ > 1) (n = 0/43) children (p ≤ 0.0001) had a TECS nutrition review. CONCLUSIONS: Dietetic reviews were severely restricted during the first national lockdown. Patients with low BMIZ prior to lockdown became more malnourished. During the ongoing pandemic, it is important to identify those children with nutrition risk, focusing support on this group of children.

Impact of COVID-19 on diagnosis and management of paediatric inflammatory bowel disease during lockdown: a UK nationwide study.

BACKGROUND: COVID-19 has impacted on healthcare provision. Anecdotally, investigations for children with inflammatory bowel disease (IBD) have been restricted, resulting in diagnosis with no histological confirmation and potential secondary morbidity. In this study, we detail practice across the UK to assess impact on services and document the impact of the pandemic. METHODS: For the month of April 2020, 20 tertiary paediatric IBD centres were invited to contribute data detailing: (1) diagnosis/management of suspected new patients with IBD; (2) facilities available; (3) ongoing management of IBD; and (4) direct impact of COVID-19 on patients with IBD. RESULTS: All centres contributed. Two centres retained routine endoscopy, with three unable to perform even urgent IBD endoscopy. 122 patients were diagnosed with IBD, and 53.3% (n=65) were presumed diagnoses and had not undergone endoscopy with histological confirmation. The most common induction was exclusive enteral nutrition (44.6%). No patients with a presumed rather than confirmed diagnosis were started on anti-tumour necrosis factor (TNF) therapy.Most IBD follow-up appointments were able to occur using phone/webcam or face to face. No biologics/immunomodulators were stopped. All centres were able to continue IBD surgery if required, with 14 procedures occurring across seven centres. CONCLUSIONS: Diagnostic IBD practice has been hugely impacted by COVID-19, with >50% of new diagnoses not having endoscopy. To date, therapy and review of known paediatric patients with IBD has continued. Planning and resourcing for recovery is crucial to minimise continued secondary morbidity.

Genetic Sequencing of Pediatric Patients Identifies Mutations in Monogenic Inflammatory Bowel Disease Genes that Translate to Distinct Clinical Phenotypes.

OBJECTIVES: Monogenic inflammatory bowel disease (IBD) comprises rare Mendelian causes of gut inflammation, often presenting in infants with severe and atypical disease. This study aimed to identify clinically relevant variants within 68 monogenic IBD genes in an unselected pediatric IBD cohort. METHODS: Whole exome sequencing was performed on patients with pediatric-onset disease. Variants fulfilling the American College of Medical Genetics criteria as "pathogenic" or "likely pathogenic" were assessed against phenotype at diagnosis and follow-up. Individual patient variants were assessed and processed to generate a per-gene, per-individual, deleteriousness score. RESULTS: Four hundred one patients were included, and the median age of disease-onset was 11.92 years. In total, 11.5% of patients harbored a monogenic variant. TRIM22-related disease was implicated in 5 patients. A pathogenic mutation in the Wiskott-Aldrich syndrome (WAS) gene was confirmed in 2 male children with severe pancolonic inflammation and primary sclerosing cholangitis. In total, 7.3% of patients with Crohn's disease had apparent autosomal recessive, monogenic NOD2-related disease. Compared with non-NOD2 Crohn's disease, these patients had a marked stricturing phenotype (odds ratio 11.52, significant after correction for disease location) and had undergone significantly more intestinal resections (odds ratio 10.75). Variants in ADA, FERMT1, and LRBA did not meet the criteria for monogenic disease in any patients; however, case-control analysis of mutation burden significantly implicated these genes in disease etiology. DISCUSSION: Routine whole exome sequencing in pediatric patients with IBD results in a precise molecular diagnosis for a subset of patients with IBD, providing the opportunity to personalize therapy. NOD2 status informs risk of stricturing disease requiring surgery, allowing clinicians to direct prognosis and intervention.

Children and young people with inflammatory bowel disease attend less school than their healthy peers.

OBJECTIVE: Chronic diseases, such as inflammatory bowel disease (IBD), can impact negatively on education and social development. Examining the impact of IBD on school/college attendance for children and young people (CYP) is vital to provide targeted support to patients, families and schools. METHODS: We performed a cross-sectional survey to determine the school/college attendance rates, the reasons for absence related to IBD and facilitators or barriers to school/college attendance. In a subset of patients followed up locally, we performed a detailed review of hospital attendance data to assess healthcare burden. RESULTS: Two hundred and thirty-one questionnaires were given to CYP with IBD aged 5-17 years. Response rate was 74% (final sample 169). The median school/college attendance rate was 92.5%, significantly lower than all children in England (95.2%). 39.6% of children with IBD were persistently absent, defined nationally as missing 10% or more of school. Only five children (3%) had a 100% attendance record. Increasing age and use of monoclonal therapy were predictors of poor school attendance. Concerns about feeling unwell at school/college, access to toilets, keeping up with work and teachers' understanding of IBD are the main issues for CYP with IBD. There was a significant negative correlation between number of days in hospital and school attendance. CONCLUSION: IBD has a significant impact on school/college attendance, with hospital attendance, disease burden and school difficulties being major factors. Employing strategies to minimise healthcare burden and developing a partnership between health and education to support children with IBD will serve to facilitate school/college attendance.

Review article: the genetics of the human leucocyte antigen region in inflammatory bowel disease.

BACKGROUND: The human leucocyte antigen (HLA) complex, located at chromosome 6p21.3 is a highly polymorphic region containing the classical class I and II HLA genes. The region is highly associated with inflammatory bowel disease (IBD), largely through genome-wide association studies (GWAS). AIMS: To review the role of HLA in immune function, summarise data on risk/protective HLA genotypes for IBD, discuss the role of HLA in IBD pathogenesis, treatment and examine limitations that might be addressed by future research. METHODS: An organised search strategy was used to collate articles describing HLA genes in IBD, including Crohn's disease and ulcerative colitis. RESULTS: All classical HLA genes with variation (including HLA-A, B, C, DRB1, DQA1, DQB1, DPA1 and DPB1) harbour IBD-associated genotypes. The most implicated gene is HLA-DRB1, with HLA-DRB1*03:01 the most associated risk allele in both Crohn's disease and ulcerative colitis. Elucidating precise disease associations is challenging due to high linkage disequilibrium between HLA genotypes. The mechanisms by which risk alleles cause disease are multifactorial, with the best evidence indicating structural and electrostatic alteration impacting antigen binding and downstream signalling. Adverse medication events have been associated with HLA genotypes including with thiopurines (pancreatitis) and anti-TNF agents (antibody formation). CONCLUSIONS: The HLA complex is associated with multiple risk/protective alleles for IBD. Future research utilising long-read technology, ascertainment of zygosity and integration in disease modelling will improve the functional understanding and clinical translation of genetic findings.

Increased prevalence of anti-TNF therapy in paediatric inflammatory bowel disease is associated with a decline in surgical resections during childhood.

BACKGROUND: Anti-tumour necrosis factor-α (anti-TNF) therapy use has risen in paediatric-onset inflammatory bowel disease (PIBD). Whether this has translated into preventing/delaying childhood surgery is uncertain. The Wessex PIBD cohort was analysed for trends in anti-TNF-therapy and surgery. AIM: To assess patients diagnosed with PIBD within Wessex from 1997 to 2017. The prevalence of anti-TNF-therapy and yearly surgery rates (resection and perianal) during childhood (<18 years) were analysed (Pearson's correlation, multivariate regression, Fisher's exact). RESULTS: Eight-hundred-and-twenty-five children were included (498 Crohn's disease, 272 ulcerative colitis, 55 IBD-unclassified), mean age at diagnosis 13.6 years (1.6-17.6), 39.6% female. The prevalence of anti-TNF-treated patients increased from 5.1% to 27.1% (2007-2017), P = 0.0001. Surgical resection-rate fell (7.1%-1.5%, P = 0.001), driven by a decrease in Crohn's disease resections (8.9%-2.3%, P = 0.001). Perianal surgery and ulcerative colitis resection-rates were unchanged. Time from diagnosis to resection increased (1.6-2.8 years, P = 0.028) but mean age at resection was unchanged. Patients undergoing resections during childhood were diagnosed at a younger age in the most recent 5 years (2007-2011 = 13.1 years, 2013-2017 = 11.9 years, P = 0.014). Resection-rate in anti-TNF-therapy treated (16.1%) or untreated (12.2%) was no different (P = 0.25). Patients started on anti-TNF-therapy <3 years post-diagnosis (11.6%) vs later (28.6%) had a reduction in resections, P = 0.047. Anti-TNF-therapy prevalence was the only significant predictor of resection-rate using multivariate regression (P = 0.011). CONCLUSIONS: The prevalence of anti-TNF-therapy increased significantly, alongside a decrease in surgical resection-rate. Patients diagnosed at younger ages still underwent surgery during childhood. Anti-TNF-therapy may reduce the need for surgical intervention in childhood, thereby influencing the natural history of PIBD.

Intestinal failure: the evolving demographic and patient outcomes on home parenteral nutrition.

AIM: We performed this study to examine and understand the evolving demographics and changing outcomes of intestinal failure (IF) and its implications for healthcare delivery. METHOD: We conducted a retrospective analysis of outcome data of children on home parenteral nutrition (HPN), over a 15-year period. RESULTS: A total of 31 patients received HPN: 15 for short bowel syndrome (SBS), eight neuromuscular disease (NMD) and eight for other causes. The HPN prevalence increased from 1.54 per million children in 2000 to 21.5 in 2016. The outcomes over last 5 years were better than those of previous 10 years. The rate of catheter-related bloodstream infection (CRBSI) had fallen from 4 to 1.3 and IF liver disease (IFALD) from 20% to 7.7%. The aetiology changed over years from SBS being the main cause to NMD contributing 43% to the total in 2016. This was especially relevant as NMD was associated with greater numbers of IFALD (38% vs 6.7%), CRBSI (1.51 vs 0.64/1000 PN days) and mortality. CONCLUSION: The outcome of long-term parenteral nutrition (PN) has improved. The increasing number of patients with NMD, coupled with their higher burden of care, results in an increasing health care burden, and the planning of intestinal rehabilitation services needs to reflect this.

Compliance with nutrition screening in a children's hospital.

INTRODUCTION: There has been an increased emphasis on the nutritional care of children in hospital with the recognition that those admitted to hospital, particularly with chronic conditions, are at significant nutrition risk. However, although nutrition risk screening tools (NRST) are widely used in acute hospital settings compliance with their use is poorly reported. METHODS: One-day cross-sectional audit of anthropometry/NRST records, Southampton Children's Hospital. Inclusion criteria were all in-patients present on the ward between 8 am and 4 pm. Comparison was made with previous data. RESULTS: One hundred and thirteen records were reviewed. Anthropometric measures; weight recorded in 96.4% length/height recorded in 64% . This reflects a significant improvement on previous length/height data of 19%. Compliance with NRST was poor; only 17% of records were completed. CONCLUSION: Compliance with basic anthropometry was high and better than previously reported although use of nutritional screening tools was poor. This raises questions about the usefulness of current tools in clinical practice and whether measurement of height, weight and assessment of intake and nutrition risk may be more appropriate.

Epidemiology, management and outcome of ultrashort bowel syndrome in infancy.

Ultrashort bowel syndrome (USBS) is a group of heterogeneous disorders where the length of small bowel is less than 10 cm or 10% of expected for the age. It is caused by massive loss of the gut which in the neonatal period can be a result of vanishing gastroschisis or surgical resection following mid-gut volvulus, jejunoileal atresia and/or extensive necrotising enterocolitis. The exact prevalence of USBS is not known although there is a clear trend towards increasing numbers because of increased incidence and improved survival. Long-term parenteral nutrition (PN) is the mainstay of treatment and is best delivered by a multidisciplinary intestinal rehabilitation team. Promoting adaptation is vital to improving long-term survival and can be achieved by optimising feeds, reducing intestinal failure liver disease and catheter-related bloodstream infections. Surgical techniques that can promote enteral tolerance and hence improve outcome include establishing intestinal continuity and bowel lengthening procedures. The outcome for USBS is similar to patients with intestinal failure due to other causes and only a small proportion of children who develop irreversible complications of PN and will need intestinal transplantation. In this review, we will summarise the available evidence focusing particularly on the epidemiology, management strategies and outcome.

Exome analysis of patients with concurrent pediatric inflammatory bowel disease and autoimmune disease.

BACKGROUND: Pediatric Inflammatory Bowel Disease (PIBD) is a chronic condition seen in genetically predisposed individuals. Genome-wide association studies have implicated >160 genomic loci in IBD with many genes coding for proteins in key immune pathways. This study looks at autoimmune disease burden in patients diagnosed with PIBD and interrogates exome data of a subset of patients. METHODS: Patients were recruited from the Southampton Genetics of PIBD cohort. Clinical diagnosis of autoimmune disease in these individuals was ascertained from medical records. For a subset of patients with PIBD and concurrent asthma, exome data was interrogated to ascertain the burden of pathogenic variants within genes implicated in asthma. Association testing was conducted between cases and population controls using the SKAT-O test. RESULTS: Forty-nine (28.3%) PIBD children (18.49% CD, 8.6% UC, and 21.15% IBDU patients) had a concurrent clinical diagnosis of at least one other autoimmune disorder; asthma was the most prevalent, affecting 16.2% of the PIBD cohort. Rare and common variant association testing revealed 6 significant genes (P < 0.05) before Bonferroni adjustment. Three of these genes were previously implicated in both asthma and IBD (ZPBP2 IL1R1, and IL18R1) and 3 in asthma only (PYHIN1, IL2RB, and GSTP1). CONCLUSIONS: One-third of our cohort had a concurrent autoimmune condition. We observed higher incidence of asthma compared with the overall pediatric prevalence. Despite a small sample size, SKAT-O evaluated a significant burden of rare and common mutations in 6 genes. Variant burden suggests that a systemic immune dysregulation rather than organ-specific could underpin immune dysfunction for a subset of patients.

Parental knowledge of coeliac disease.

AIM: Little information exists regarding parental knowledge of CD at diagnosis. We aimed for assessment of parental information at disease diagnosis to help us develop a tailored coeliac information package. METHODS: Children and teenagers referred for endoscopy and duodenal biopsy, with the sole indication for the diagnosis of CD, were prospectively recruited to the study. Parents were asked information and concerns regarding use of GFD. RESULTS: Sixty-three children (median 6.9 yrs (IQR 3.71-10.94)) and families were prospectively recruited in the study. The parents were very knowledgeable with an impressive 98% of the parents understanding that GFD is the treatment of CD; 95% knowing that this treatment is for life. However, specific dietary information was lacking with one-third correctly identifying all the Gluten containing foods. Internet (70.6%) was the most common source of information. Knowing someone with CD (p = 0.038), particularly in the same household in the family (p = 0.013) and researching about the disease (p = 0.001) rather than level of parental education (p = ns) was predictive of better parental knowledge. CONCLUSION: Internet is a major influence to parental knowledge in today's age but there is a continued need for hospitals regarding provision of accurate information and alleviating anxieties regarding use of GFD.

A very high amylase can be benign in paediatric Crohn's disease.

A 12.5-year-old boy with Crohn's disease with abdominal pain had a raised amylase of 1835 IU/l with normal lipase levels. Ultrasound showed no evidence of inflammation of pancreas. The amylase to creatinine clearance ratio, was 0.8% (reference interval 2%-5%; >6% consistent with acute pancreatitis; <1.6% with macroamylasemia), suggesting he had raised serum amylase with a corresponding reduced clearance of amylase in his urine, positively supporting the diagnosis of macroamylasemia. Macroamylasemia has no clinical significance other than misdiagnosis as acute pancreatitis. Awareness of this condition is important and a positive diagnosis should always be made to avoid unnecessary changes in treatments.

Current therapy of ulcerative colitis in children.

Ulcerative colitis presents in childhood in 10% of those affected, usually with pancolitis. Important features in management include growth, development and avoidance of treatment toxicity. This review addresses the current treatment options including both the paediatric evidence-based experience and areas where paediatric practice is informed by adult studies. Standard treatments include sulfasalazine or 5-aminosalicylates, corticosteroids, purine derivatives (azathioprine or 6-mercaptopurine) and surgery. Other immunosuppressant therapies and the emerging roles for biological therapies and probiotics are discussed.