Normalization of C1 Inhibitor in a Patient with Hereditary Angioedema.

Hereditary angioedema is a potentially life-threatening autosomal dominant condition, causing attacks of angioedema due to failure to regulate bradykinin. Nearly all cases of hereditary angioedema are caused by mutations in the gene encoding C1 inhibitor, SERPING1. C1 inhibitor is a multifunctional protein produced in the liver that regulates the kallikrein-kinin system at multiple points. An infant with genetically confirmed hereditary angioedema and low C1 inhibitor levels (but without previous episodes of angioedema) underwent liver transplantation for biliary atresia, an unrelated condition. Liver transplantation led to normalization of the C1 inhibitor level and function. To our knowledge, this represents the first patient to be potentially cured of hereditary angioedema.

Adaptations to the current ECCO/ESPGHAN guidelines on the management of paediatric acute severe colitis in the context of the COVID-19 pandemic: a RAND appropriateness panel.

OBJECTIVE: Paediatric acute severe colitis (ASC) management during the novel SARS-CoV-2/COVID-19 pandemic is challenging due to reliance on immunosuppression and the potential for surgery. We aimed to provide COVID-19-specific guidance using the European Crohn's and Colitis Organisation/European Society for Paediatric Gastroenterology, Hepatology and Nutrition guidelines for comparison. DESIGN: We convened a RAND appropriateness panel comprising 14 paediatric gastroenterologists and paediatric experts in surgery, rheumatology, respiratory and infectious diseases. Panellists rated the appropriateness of interventions for ASC in the context of the COVID-19 pandemic. Results were discussed at a moderated meeting prior to a second survey. RESULTS: Panellists recommended patients with ASC have a SARS-CoV-2 swab and expedited biological screening on admission and should be isolated. A positive swab should trigger discussion with a COVID-19 specialist. Sigmoidoscopy was recommended prior to escalation to second-line therapy or colectomy. Methylprednisolone was considered appropriate first-line management in all, including those with symptomatic COVID-19. Thromboprophylaxis was also recommended in all. In patients requiring second-line therapy, infliximab was considered appropriate irrespective of SARS-CoV-2 status. Delaying colectomy due to SARS-CoV-2 infection was considered inappropriate. Corticosteroid tapering over 8-10 weeks was deemed appropriate for all. After successful corticosteroid rescue, thiopurine maintenance was rated appropriate in patients with negative SARS-CoV-2 swab and asymptomatic patients with positive swab but uncertain in symptomatic COVID-19. CONCLUSION: Our COVID-19-specific adaptations to paediatric ASC guidelines using a RAND panel generally support existing recommendations, particularly the use of corticosteroids and escalation to infliximab, irrespective of SARS-CoV-2 status. Consideration of routine prophylactic anticoagulation was recommended.

Transition Services for Paediatric Inflammatory Bowel Disease: A Multicentre Study of Practice in the United Kingdom.

OBJECTIVES: Patients with paediatric inflammatory bowel disease (IBD) constitute one of the largest cohorts requiring transition from paediatric to adult services. Standardised transition care improves short and long-term patient outcomes. This study aimed to detail the current state of transition services for IBD in the United Kingdom (UK). METHODS: We performed a nationwide study to ascertain current practice, facilities and resources for children and young people with IBD. Specialist paediatric IBD centres were invited to contribute data on: timing of transition/transfer of care; transition resources available including clinics, staff and patient information; planning for future improvement. RESULTS: Twenty of 21 (95%) of invited centres responded. Over 90% of centres began the transition process below 16 years of age and all had completed transfer to adult care at 18 years of age. The proportion of patients in the transition process at individual centres varied from 10% to 50%.Joint clinics were held in every centre, with a mean of 12.9 clinics per year. Adult and paediatric gastroenterologists attended at all sites. Availability of additional team members was patchy across the UK, with dietetic, psychological and surgical attendance available in <50% centres. A structured transition tool was used in 75% of centres. Sexual health, contraception and pregnancy were discussed by <60% of teams. CONCLUSIONS: This study provides real-world clinical data on UK-wide transition services. These data can be used to develop a national strategy to complement current transition guidelines, focused on standardising services whilst allowing for local implementation.

Paediatric Colonoscopy Direct Observation of Procedural Skills: Evidence of Validity and Competency Development.

INTRODUCTION: The paediatric series of direct observation of procedural skills (DOPS) were introduced into the UK national endoscopy training curriculum in 2016, but lack validity evidence. We aimed to present validity evidence for paediatric colonoscopy DOPS and study competency development in a national trainee cohort. METHODS: This prospective UK-wide study analysed formative paediatric colonoscopy DOPS which were submitted to the e-Portfolio between 2016 and 2018. Item, domain, and average DOPS scores were correlated with the overall DOPS rating to evidence internal structure validity. Overall DOPS ratings were compared over lifetime procedure count to demonstrate learning curves (discriminant validity). Consequential validity was founded on receiver operating characteristic curve analyses. RESULTS: A total of 203 DOPS assessments were completed for 29 trainees from 11 UK training centres. Internal structure validity was provided through item-total correlation analyses. DOPS scores positively correlated with trainee seniority (P < 0.001) and lifetime procedure count (P < 0.001). Competency acquisition followed the order of: "preprocedure," "postprocedure," "endoscopic nontechnical skills," "management," "procedure" domains, followed by overall DOPS competency, which was achieved in 81% of the cohort after 125 to 149 procedures. Mean DOPS scores could be used to predict overall procedure competence (area under receiver operating characteristic curve 0.969, P < 0.001), with a mean score of 3.9 demonstrating optimal sensitivity (93.5%) and specificity (87.6%). CONCLUSIONS: This study provides validity evidence supporting the use of paediatric colonoscopy DOPS as an in-training competence assessment tool. DOPS may also be used to measure competency development and benchmark performance during training, which may be of value to trainees, trainers, and training programmes.

Paediatric Endoscopy Global Rating Scale: Development of a Quality Improvement Tool and Results of a National Pilot.

INTRODUCTION AND OBJECTIVES: The endoscopy Global Rating Scale (GRS) is a web-based self-assessment quality improvement (QI) tool that provides a framework for service improvement. Widespread use of the GRS in adult endoscopy services in the United Kingdom (UK) has led to a demonstrable improvement in quality. The adult GRS is not directly applicable to paediatric endoscopy services. The objective of this study is to develop and pilot a paediatric endoscopy Global Rating Scale (P-GRS) as a QI tool. METHODS: Members of the British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) Endoscopy Working Group collaborated with the Joint Advisory Group on Gastrointestinal Endoscopy (JAG) to develop the P-GRS. After a period of consultation, this was piloted nationally at 9 centres and data were collected prospectively at 2 census points, May and December 2016. RESULTS: The P-GRS mirrors the adult GRS by dividing care into 4 domains and includes 19 standards with several measures that underpin the standards. Eight services completed the online P-GRS return in May 2016 and 6 in December 2016. All pilot sites identified areas that needed improvement and post-pilot reflected on the key challenges and developments. Several positive developments were reported by the pilot sites. CONCLUSIONS: The national pilot helped ensure that the P-GRS developed was relevant to the paediatric endoscopy services. The pilot demonstrated that even in the first year of engaging with this QI tool, services were starting to identify areas that needed improvement, share best practice documents, put in place QI plans, and support greater patient involvement in services.

Validity Evidence for Direct Observation of Procedural Skills in Paediatric Gastroscopy.

OBJECTIVES: Direct observation of procedural skills (DOPS) are competence-assessment tools in endoscopy. Formative paediatric gastroscopy DOPS were implemented into the UK curriculum in 2016 but lack validity evidence; we aimed to assess validity evidence using a recognised contemporary validity framework. METHODS: We performed a prospective UK-wide analysis of formative paediatric gastroscopy DOPS submitted to the e-Portfolio over 1 year. Internal structure validity was assessed using interitem correlations between DOPS items, average domain, and skillset scores and with the overall competency rating. Overall competence scores and mean DOPS scores were compared by trainee seniority and procedure count (discriminative validity). Receiver operating characteristic curve analysis was performed to explore if DOPS scores could be used to delineate procedural competency (consequential validity). RESULTS: A total of 157 DOPS assessments were completed by 20 trainers for 17 trainees. Strengths of correlations varied between DOPS components, with overall competency correlating most with technical-predominant items, domains and skillsets. Both the overall assessor's rating and mean DOPS scores increased with trainee seniority (P < 0.001) and lifetime procedure count (P < 0.001). Overall competency could be delineated using mean DOPS scores (area under receiver operating characteristic curve 0.95, P < 0.001), with a threshold of 3.9 providing optimal sensitivity (94.4%) and specificity (89.7%). CONCLUSIONS: Competencies in paediatric gastroscopy, as assessed using DOPS, vary in their correlation with overall competence and increase with trainee experience. Formative DOPS thresholds could be used to indicate readiness for summative assessment. Our study therefore provides evidence of internal structure, discriminative, and consequential validity in support of formative paediatric gastroscopy DOPS.

Retrospective review of effectiveness and safety of intravenous ferric carboxymaltose given to children with iron deficiency anaemia in one UK tertiary centre.

In the paediatric population, ferric carboxymaltose (FCM) is only licenced for use in children older than 14 years, and the data in younger children remains scarce. We retrospectively reviewed data of all paediatric patients less than 14 years old who had received FCM infusion from August 2011 to June 2015 at the John Radcliffe Hospital (Oxford University Hospitals), UK. The patient demographics, significant medical history, FCM dose, and blood investigations (pre-FCM and post-FCM) were reviewed. Of the 51 children, 41 had inflammatory bowel disease. There were 24 girls and 27 boys, aged 1 to 13 years, mean (SD) weight 28.4 (13.6) kg. Fifteen patients received at least one more course of FCM up to 35 months later. The time interval between pre-FCM and post-FCM investigations was 1 to 8 months. An improved, median (range) rise in blood indices following one FCM infusion was haemoglobin 2.7 (- 2.4 to 7) g/dL, serum iron 6.6 (- 0.6 to 21.1) µmol/L, and transferrin saturation 14 (- 14 to 38)%. No adverse outcomes were documented. CONCLUSIONS: FCM was effective in increasing the key blood indices with no adverse outcomes in children less than 14 years of age, with a range of different conditions, majority with gastrointestinal disorders such as IBD. What is Known: • Ferric carboxymaltose (FCM) given via the intravenous (IV) route has been used widely in adults for the treatment of iron deficiency anaemia. • Sparse data exists on FCM use in paediatric population, including young children What is New: • FCM infusion should be considered as a means of iron administration in the paediatric population less than 14 years of age • No adverse outcomes were recorded following FCM in a young paediatric population (less than 14 years of age); the majority of whom had gastrointestinal disorders.

Sustained Increase in Pediatric Inflammatory Bowel Disease Incidence Across the South West United Kingdom Over the Last 10 Years.

BACKGROUND: Pediatric inflammatory bowel disease (pIBD) incidence has increased over the last 25 years. We aim to report contemporaneous trends across the South West United Kingdom. METHODS: Data were provided from centers covering the South West United Kingdom (Bristol, Oxford, Cardiff, Exeter, and Southampton), with a total area at-risk population (<18 years of age) of 2 947 534. Cases were retrieved from 2013 to 2022. Incident rates were reported per 100 000 at-risk population, with temporal trends analyzed through correlation. Subgroup analysis was undertaken for age groups (0-6, 6-11, and 12-17 years of age), sex, and disease subtype. Choropleth maps were created for local districts. RESULTS: In total, 2497 pIBD cases were diagnosed between 2013 and 2022, with a mean age of 12.6 years (38.7% female). Diagnosis numbers increased from 187 to 376, with corresponding incidence rates of 6.0 per 100 000 population per year (2013) to 12.4 per 100 000 population per year (2022) (b = 0.918, P < .01). Female rates increased from 5.1 per 100 000 population per year in 2013 to 11.0 per 100 000 population per year in 2022 (b = 0.865, P = .01). Male rates increased from 5.7 per 100 000 population per year to 14.4 per 100 000 population per year (b = 0.832, P = .03). Crohn's disease incidence increased from 3.1 per 100 000 population per year to 6.3 per 100 000 population per year (b = 0.897, P < .01). Ulcerative colitis increased from 2.3 per 100 000 population per year to 4.3 per 100 000 population per year (b = 0.813, P = .04). Inflammatory bowel disease unclassified also increased, from 0.6 per 100 000 population per year to 1.8 per 100 000 population per year (b = 0.851, P = .02). Statistically significant increases were seen in those ≥12 to 17 years of age, from 11.2 per 100 000 population per year to 24.6 per 100 000 population per year (b = 0.912, P < .01), and the 7- to 11-year-old age group, with incidence rising from 4.4 per 100 000 population per year to 7.6 per 100 000 population per year (b = 0.878, P = .01). There was no statistically significant increase in very early onset inflammatory bowel disease (≤6 years of age) (b = 0.417, P = .231). CONCLUSIONS: We demonstrate significant increases in pIBD incidence across a large geographical area including multiple referral centers. Increasing incidence has implications for service provision for services managing pIBD.

Incidence of inflammatory bowel disease continues to increase in childhood, particularly in older children. This is demonstrated in a contemporary dataset collected over a 10-year period, and covering an at-risk population of nearly 3 000 000. These data have significant implications for service provision.

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.

Intestinal failure following necrotizing enterocolitis: A clinical approach.

Intestinal failure is a recognized complication of surgically-managed necrotizing enterocolitis (NEC). Functional adaptation of remaining bowel means that many children are eventually able to achieve enteral autonomy. Integrated multidisciplinary care in the early post-operative phase is key to long-term success. The objective of this review is to outline a clinical approach to management of intestinal and nutritional complications experienced by children following intestinal resection for NEC.

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.

Tubulointerstitial nephritis and uveitis in monozygotic twin boys.

We describe monozygotic male twins who developed tubulointerstitial nephritis and uveitis (TINU) almost 2 years apart. They presented with non-specific symptoms and were noted to have glycosuria and renal impairment. Both children have uveitis. One had biopsy-proven interstitial nephritis and the other had biochemical evidence of transient tubular dysfunction. While the renal parameters improved, they are still under treatment for uveitis. The occurrence of TINU in identical twins at an interval of just under 2 years supports a strong genetic element in the aetiology of this syndrome. We believe this is the first report of male twins with TINU.

Interleukin-11 levels in healthy and thrombocytopenic neonates.

Thrombocytopenia is common in sick neonates, and affected neonates have adverse outcomes compared with those without thrombocytopenia. As impaired platelet production underlies many neonatal thrombocytopenias, affected neonates are potential candidates for hemopoietic growth factor therapy. Although recombinant human (rh) thrombopoietin remains under therapeutic development, rhIL-11, which stimulates megakaryocytopoiesis and increases platelet counts after chemotherapy, is already licensed for clinical use. However, nothing is known about IL-11 in neonates. We therefore measured plasma IL-11 by ELISA in healthy term neonates, stable preterm neonates with or without thrombocytopenia, and preterm neonates with sepsis or necrotizing enterocolitis (NEC) with or without thrombocytopenia. At birth IL-11 was undetectable (<10 pg/mL) in healthy term neonates (n = 20) and 27 of 31 (87%) stable preterm neonates. Three stable preterm neonates with detectable IL-11 (mean+/-SD, 11.3 +/- 0.4 pg/mL; median, 11.6 pg/mL) suffered chorioamnionitis, the remaining neonate (IL-11, 14 pg/mL) being one of nine with early onset thrombocytopenia (present by <72 h of age). IL-11 was also measured in 58 preterm neonates with suspected sepsis or NEC. In 25 of 58, sepsis or NEC was unconfirmed and IL-11 was undetectable. By contrast, 14 of 33 with proven sepsis or NEC had elevated IL-11 (median, 14.9 pg/mL; range, 11.2-92.2 pg/mL). Of these 33 neonates, 19 developed thrombocytopenia: nine of 19 (47%) had detectable IL-11 and 10 of 19 (53%) did not (p > 0.05). Although its role in platelet production in neonates remains unclear, these data suggest that IL-11 is involved in the endogenous cytokine response to sepsis or NEC in preterm neonates. Further studies of IL-11 in neonates are warranted to assess its role both in platelet production and in mediation of the endogenous inflammatory response.