Safety and efficacy of parenteral iron in children with inflammatory bowel disease.

AIMS: Iron deficiency anaemia frequently complicates inflammatory bowel disease (IBD) in children and adults. Oral iron may exacerbate gastrointestinal symptoms and absorption may be insufficient in intestinal inflammation. Even where oral iron is successful, repletion of iron stores can be unacceptably slow. Intravenous iron compounds were in the past associated with serious adverse reactions and historically were considered a last resort in children. New generation preparations have a safer profile in adults, although reluctance to use them in children may persist, where safety data are lacking. We investigate the safety and efficacy of ferric carboxymaltose and iron sucrose in children. METHODS: We retrospectively identified all children with IBD who received parenteral iron over a 38-month period in a single regional referral centre. Safety, tolerability and adverse events were established by case note review. Efficacy was assessed by change in haematinic indices pre- and post-treatment. RESULTS: Forty-one children (18 male; median age 14 years, range 3-17) received a total of 104 iron infusions. Of these, 44% (18) had Crohn's disease; 56% (23) ulcerative colitis. Thirty-five received ferric carboxymaltose, seven iron sucrose and one both. Three children developed mild rash post infusion which resolved quickly with chlorphenamine. Mean increase in haemoglobin was 2.5 g dl-1 (0.3-5.8). Iron levels increased by a mean of 8.4 g dl-1 (1-25), transferrin saturation by 16.2% (2-47). Transferrin decreased by 0.84 g dl-1 (0.3-3.4). CONCLUSIONS: New generation parenteral iron preparations are safe, well tolerated and efficacious in children with iron deficiency anaemia and IBD.

Real-life Anti-tumor Necrosis Factor Experience in More Than 500 Patients: High Co-immunosuppression Rates But Low Rates of Quantifying Treatment Response.

OBJECTIVE: The aim of this study was to measure the effectiveness, safety, and use of anti-tumor necrosis Factor (TNF) therapy in pediatric inflammatory bowel disease in the United Kingdom (UK). METHODS: Prospective UK audit of patients newly starting anti-TNF therapy. Disease severity was assessed using Physician Global Assessment +/or the Paediatric Crohn Disease Activity Index. RESULTS: A total of 37 centers participated (23/25 specialist pediatric inflammatory bowel disease sites). A total of 524 patients were included: 429 with Crohn disease (CD), 76 with ulcerative colitis (UC), and 19 with IBD unclassified (IBDU). Eighty-seven percent (488/562) of anti-TNF was infliximab; commonest indication was active luminal CD 77% (330/429) or chronic refractory UC/IBDU 56% (53/95); 79% (445/562) had concomitant co-immunosuppression. In CD (267/429 male), median time from diagnosis to treatment was 1.42 years (interquartile range 0.63-2.97). Disease (at initiation) was moderate or severe in 91% (156/171) by Physician Global Assessment compared to 41% (88/217) by Paediatric Crohn Disease Activity Index (Kappa (κ) 0.28 = only "fair agreement"; P < 0.001.Where documented, 77% (53/69) of patients with CD responded to induction; and 65% (46/71) entered remission. A total of 2287 infusions and 301.96 years of patient' follow-up (n = 385) are represented; adverse events affected 3% (49/1587) infliximab and 2% (2/98) adalimumab infusions (no deaths or malignancies). Peri-anal abscess drainage was less common after anti-TNF initiation (CD), that is 26% (27/102) before, 7% (3/42) after (P = 0.01); however, pre and post anti-TNF data collection was not over equal time periods. CONCLUSIONS: Anti-TNFs are effective treatments, usually given with thiopurine co-immunosuppression. This study highlights deficiencies in formal documentation of effect and disparity between disease severity scoring tools, which need to be addressed to improve ongoing patient care.

Evolution of in vitro cow's milk protein-specific inflammatory and regulatory cytokine responses in preterm infants with necrotising enterocolitis.

BACKGROUND: We have previously reported evidence of in vitro sensitisation to cow's milk protein in peripheral blood mononuclear cells (PBMCs) in preterm infants with necrotising enterocolitis (NEC). In the present study, we document the changes in the PBMC responses to stimulation with mitogen (phytohaemagglutinin) and cow's milk proteins ß-lactoglobulin (ß-lg) and casein over time: from the acute presentation of NEC, to initial recovery (reinitiation of enteral feeds), to full recovery (full feeding). METHODS: Of the 14 preterm infants recruited with acute NEC, 12 were followed until fully enterally fed (2 died during the acute phase). Cytokine secretion (interferon-γ [IFN-γ], interleukin 4, [IL-4], IL-10, and transforming growth factor-ß1 [TGF-ß1]) by PBMCs in response to stimulation by phytohaemagglutinin, ß-lg, and casein was measured by enzyme-linked immunospot in the acute phase and subsequently at recovery and full recovery. RESULTS: The high levels of cytokine secretion (IFN-γ, IL-4, IL-10, and TGF-ß1) observed in response to ß-lg and casein in the acute phase increased by a further 50% to 100% at recovery (P < 0.005). At full recovery (full feeding), however, IFN-γ, IL-4, and IL-10 secretion response had returned to, or below, acute-phase levels, whereas the augmented TGF-ß1 response was maintained (P = 0.005 vs acute level). This response pattern was similar for casein, and did not appear to be influenced by the nature of the feed used following NEC (breast milk/formula/hydrolysed formula). CONCLUSIONS: The evolution of the cytokine response profile in parallel with the clinical recovery from NEC is consistent with a putative role for TGF-ß1 in regulation of inflammation, and possibly also oral tolerance.

In vitro cow's milk protein-specific inflammatory and regulatory cytokine responses in preterm infants with necrotizing enterocolitis and sepsis.

Enteral feeding with cow's milk formula is associated with neonatal necrotizing enterocolitis (NEC) and sepsis. Dietary antigen sensitization may play a role in promoting and/or sustaining inflammation in both conditions. Aiming at investigating cow's milk protein (CMP)-specific cytokine responses in preterm infants with NEC and sepsis, 14 babies with NEC, 14 matched healthy controls, and 10 septic controls were recruited. Unstimulated and stimulated peripheral blood mononuclear cells (PBMCs) secreting IFN-γ, IL-4, IL-10, and TGF-ß1 were counted by the single-cell enzyme-linked immunospot (ELISPOT) assay. During the acute phase of NEC, patients showed a general pattern of a high level of cytokine secretion both when unstimulated and stimulated by mitogen [phytohaemagglutinin (PHA)] and CMPs: beta-lactoglobulin (ß-lg) and casein. These responses were more marked to ß-lg for IFN-γ, IL-4, and IL-10 than TGF-ß1. Cytokine responses in sepsis were lower than in NEC (lowest in healthy controls, with a minimal TGF-ß1 response). At term, lower frequencies of cytokine-secreting cells were elicited than during the acute phase, except for TGF-ß1 secreting cells, which increased at term (in response to PHA and CMPs) particularly following not only NEC but also sepsis.

Surgery in children with Crohn disease refractory to medical therapy.

OBJECTIVE: The aim of this study was to evaluate the results of surgery in children with Crohn disease (CD) not responding to medical therapy and establish whether surgery improves growth and nutrition. PATIENTS AND METHODS: Children with CD diagnosed between 1998 and 2008 were reviewed. Relapse was defined by Harvey-Bradshaw index >5. Data, reported as median (range), were compared by Fisher exact test and repeated-measures ANOVA. RESULTS: One hundred forty-one children, ages 12.7 years (3.5-16.8), were identified; 27 (19%) required surgery 14.5 months (1.1-61.8) after diagnosis. Twenty-one had elective surgery (19 isolated ileocaecal disease and stricture, 2 diffuse disease of ileum); 6 had emergency surgery (3 peritonitis, 2 haemorrhage, 1 perforation). Surgery included 18 ileocaecal resection and end-to-end anastomosis, 5 stoma formation, 2 left hemicolectomy and end-to-end anastomosis, and 2 stricturoplasty. Follow-up was 2.5 years (1-9.4). Growth and nutrition improved by 6 and 12 months after surgery, with a significant increase in weight z score (P < 0.0001), height z score (P < 0.0001), albumin (30 [13-36] vs 39 [30-46] vs 40 [33-45], P < 0.0001), and haemoglobin [10 (6.8-13.2) vs 11.7 (8.2-13.7) vs 12.0 (9.3-14.7), P < 0.0001]. All patients of the received azathioprine (2-2.5 mg · kg⁻¹ · day⁻¹) after surgery. Fifteen patients (55%) relapsed with a modified Harvey-Bradshaw index of 8 (6-11) within 11.5 months (4.2-33.4). Of these, 5 patients (18%) relapsed within 1 year. Five patients (18%) had further surgery (2 anastomotic strictures, 2 diseased stoma, and 1 enterocutaneous fistula). CONCLUSIONS: Growth and nutrition following surgery for CD improve, but there is a high relapse rate. Despite this, the improved growth and nutrition before relapse may be beneficial during puberty and justify surgery in children not responding to medications.

Laparoscopic oesophageal cardiomyotomy without fundoplication in children with achalasia: a 10-year experience: a retrospective review of the results of laparoscopic oesophageal cardiomyotomy without an anti-reflux procedure in children with achalasia.

BACKGROUND: Oesophageal achalasia is a rare disorder in childhood. Common treatments in adults include oesophageal cardiomyotomy (laparoscopic or open) with fundoplication. We aimed to assess the results of laparoscopic oesophageal cardiomyotomy without fundoplication for treatment of achalasia in children. METHODS: We reviewed the results of laparoscopic oesophageal cardiomyotomy between January 1998 and June 2008. Patients below the age of 18 years, who had undergone laparoscopic oesophageal cardiomyotomy without an anti-reflux procedure by a single surgeon, were identified. Data were collected from patient notes. Results are reported as median (range). RESULTS: There were 20 patients (13 males and 7 females). Median age at surgery was 12 years (5-15 years) and weight was 38 kg (15-53 kg). Median duration of symptoms before surgery was 2.4 years (1.5-5 years). Duration of surgery was 96 min (60-160 min). Four patients (20%) required conversion to the open technique. In the remaining 16 children, fluids were started at a median of 7 h (6-8 h) post-operatively, and solid feeds were commenced at 22 h (20-24 h). Median length of hospital stay was 3 days (1-5 days). Median length of follow-up was 60 months (8-114 months). None of the patients had evidence of gastro-oesophageal reflux post-operatively. Five patients (25%) continued to experience dysphagia, with one of them also experiencing vomiting. Two patients were found to have oesophageal stricture and three patients were found to have oesophageal dysmotility. The remaining patients are asymptomatic. CONCLUSIONS: These results suggest that laparoscopic oesophageal cardiomyotomy is a valid treatment in children with achalasia. In our experience, an adjunctive anti-reflux procedure is not required, as there was no evidence of post-operative gastro-oesophageal reflux in all patients. Oesophageal stricture and dysmotility account for residual post-operative symptoms.

Improved Medical Treatment and Surgical Surveillance of Children and Adolescents with Ulcerative Colitis in the United Kingdom.

Background: Pediatric ulcerative colitis (UC) presents at an earlier age and increasing prevalence. Our aim was to examine morbidity, steroid sparing strategies, and surgical outcome in children with active UC. Methods: A national prospective audit was conducted for the inpatient period of all children with UC for medical or surgical treatment in the United Kingdom (UK) over 1 year. Thirty-two participating centers recruited 224 children in 298 admissions, comparisons over 6 years were made with previous audits. Results: Over 6 years, recording of Paediatric Ulcerative Colitis Activity Index (PUCAI) score (median 65)(23% to 55%, P < 0.001), guidelines for acute severe colitis (43% to 77%, P < 0.04), and ileal pouch surgery registration (4% to 56%, P < 0.001) have increased. Corticosteroids were given in 183/298 episodes (61%) with 61/183 (33%) not responding and requiring second line therapy or surgery. Of those treated with anti-TNFalpha (16/61, 26%), 3/16 (18.8%) failed to respond and required colectomy. Prescription of rescue therapy (26% to 49%, P = 0.04) and proportion of anti-TNFalpha (20% to 53%, P = 0.03) had increased, colectomy rate (23.7% to 15%) was not significantly reduced (P = 0.5). Subtotal colectomy was the most common surgery performed (n = 40), and surgical complications from all procedures occurred in 33%. In 215/224 (96%) iron deficiency anemia was detected and in 51% treated, orally (50.2%) or intravenously (49.8%). Conclusions: A third of children were not responsive to steroids, and a quarter of these were treated with anti-TNFalpha. Colectomy was required in 41/298 (13.7%) of all admissions. Our national audit program indicates effectiveness of actions taken to reduce steroid dependency, surgery, and iron deficiency. 10.1093/ibd/izy042_video1izy042.video15769503407001.

Oral Iron Treatment Response and Predictors in Anaemic Adolescents and Adults with IBD: A Prospective Controlled Open-Label Trial.

BACKGROUND: Because of previous concerns about the efficacy and safety of oral iron for treating iron deficiency anaemia in inflammatory bowel disease [IBD], particularly in young people, we compared the effects of ferrous sulphate on haemoglobin response, disease activity and psychometric scores in adolescents and adults with IBD. We also assessed the relation of baseline serum hepcidin to haemoglobin response. METHODS: We undertook a prospective, open-label, 6-week non-inferiority trial of the effects of ferrous sulphate 200 mg twice daily on haemoglobin, iron status, hepcidin, disease activity (Harvey-Bradshaw Index, Simple Colitis Clinical Activity Index, C-reactive protein [CRP]), faecal calprotectin and psychometric scores in 45 adolescents [age 13-18 years] and 43 adults [>18 years]. RESULTS: On intention-to-treat analysis, ferrous sulphate produced similar rises in haemoglobin in adolescents {before treatment 10.3 g/dl [0.18] (mean [SEM]), after 11.7 [0.23]: p < 0.0001} and adults (10.9 g/dl [0.14], 11.9 [0.19]: p < 0.0001); transferrin saturation, ferritin [in adolescents] and hepcidin [in adults] also increased significantly. On per-protocol univariate analysis, the haemoglobin response was inversely related to baseline haemoglobin, CRP and hepcidin. Oral iron did not alter disease activity; it improved Short IBDQ and Perceived Stress Questionnaire scores in adults. CONCLUSION: Oral ferrous sulphate was no less effective or well-tolerated in adolescents than adults, and did not increase disease activity in this short-term study. The inverse relation between baseline CRP and hepcidin levels and the haemoglobin response suggests that CRP or hepcidin measurements could influence decisions on whether iron should be given orally or intravenously. [ClinTrials.gov registration number NCT01991314].

Management of ulcerative colitis.

Ulcerative colitis (UC) in children is increasing. The range of treatments available has also increased too but around 1 in 4 children still require surgery to control their disease. An up-to-date understanding of treatments is essential for all clinicians involved in the care of UC patients to ensure appropriate and timely treatment while minimising the risk of complications and side effects.

Age-related alterations in blood and colonic dendritic cell properties.

BACKGROUND: Dendritic cells (DC) determine initiation, type and location of immune responses and, in adults, show decreased Toll-like receptors and some increased cytokine levels on ageing. Few studies in children have characterised DC or explored DC-related mechanisms producing age-related immune changes. RESULTS: The pDC marker BDCA2 (but not CD123) was absent in pre-pubertal children and numbers of pDC decreased with age. Blood and colonic DC were more mature and activated in adults. Decrease in pDC numbers correlated with reduced GM-CSF levels with aging, but increasing IL-4 and IL-8 levels correlated with a more activated DC profile in blood. CXCL16 levels decreased with age. METHODS: Blood and colonic DC phenotypes were determined in healthy adults and children by flow cytometry and correlated with aging. Blood DC were divided into plasmacytoid (pDC) and myeloid (mDC) while only mDC were identified in colon. Serum cytokine levels were determined by multiplex cytokine assays and correlated with DC properties. CONCLUSIONS: In children, lack of BDCA2, a receptor mediating antigen capture and inhibiting interferon induction, may be immunologically beneficial during immune development. Conversely, reduced pDC numbers, probably secondary to decreasing GM-CSF and increasing cytokine-induced maturation of DC are likely to determine deteriorating immunity with ageing.

Treatment Options and Outcomes of Pediatric IBDU Compared with Other IBD Subtypes: A Retrospective Multicenter Study from the IBD Porto Group of ESPGHAN.

BACKGROUND: Inflammatory bowel disease unclassified (IBDU) is the rarest IBD subtype with treatment based on extrapolation from ulcerative colitis (UC) and Crohn's disease (CD) studies. We compared IBDU treatment choices with other colonic IBDs and explored long-term outcomes. METHODS: This was a multicenter retrospective longitudinal study of 23 centers of pediatric IBD with isolated colitis, including a mild ileitis consistent with backwash. RESULTS: Of note, 797 children (median age: 11.6 years, range: 2-18.4) were included: 250 with CD, 287 with UC, and 260 with IBDU (median follow-up: 2.8 [interquartile range: 1.6-4.2] years). IBDU differed from UC with lower corticosteroid (154 [59%] versus 204 [71%]; P = 0.004) and higher exclusive enteral nutrition use (26 [10%] versus 2 [0.6%]; P < 0.0001). Compared to patients with CD, patients with IBDU received less exclusive enteral nutrition and immunomodulators (26 [10%] versus 93 [37%]; P < 0.0001 and 67 [26%] versus 129 [52%]; P < 0.0001, respectively) but more aminosalicylates (228 [88%] versus 159 [64%]; P < 0.0001). Biological treatment was significantly higher in CD (82 [34%]) than in IBDU and UC (24 [12%] and 47 [17%], respectively; P < 0.0001). At last follow-up, 135 (69%) patients with IBDU had remission/mild disease activity compared with 100 (46%; P < 0.0001) patients with CD and 174 (64%; P = 0.3) patients with UC. Four (2%) of 194 patients with IBDU underwent surgery compared with 22 (8%) of 270 patients with UC (P = 0.009) and 20 (8%) of 238 patients with CD (P = 0.008). CONCLUSIONS: Children with IBDU have a lower medication burden and lower surgery rates than other IBD subtypes. The disease course at follow-up is generally mild, supporting an initial trial with 5-ASA before using more aggressive therapies.

Control of systemic and local inflammation with transforming growth factor beta containing formulas.

Enteral nutrition therapy with liquid diet has been shown to be effective in achieving clinical remission in intestinal Crohn's disease. The mechanism of action of this therapy, however, is still poorly understood. As part of our assessment of the action of 3 related polymeric enteral therapies, we have used a variety of techniques to document the histological and cytokine responses, in the mucosa and, systemically, to these treatments. The feeds studied (AL110, Modulen IBD and ACD004 [Nestle, Vevey, Switzerland]) all have casein as the protein source, are lactose free and are rich in transforming growth factor beta (TGF-beta). They have all been shown to induce clinical remission associated with mucosal healing. In the case of Modulen IBD, as well as mucosal macroscopic and histological healing there was a fall in mucosal proinflammatory cytokines: interleukin-1 mRNA in colonic and ileal, interleukin-8 mRNA in the colon and interferon gamma mRNA in the ileum, but a rise in the regulatory cytokine TGF-beta mRNA in the ileum. These results indicate that these formulas are influencing the disease process itself, and thus suggest that the clinical remission achieved is a result of a reduction in inflammation, rather than a consequence of some other nutrition effect.

Disease phenotype at diagnosis in pediatric Crohn's disease: 5-year analyses of the EUROKIDS Registry.

BACKGROUND: It has been speculated that pediatric Crohn's disease (CD) is a distinct disease entity, with probably different disease subtypes. We therefore aimed to accurately phenotype newly diagnosed pediatric CD by using the pediatric modification of the Montreal classification, the Paris classification. METHODS: Information was collected from the EUROKIDS registry, a prospective, web-based registry of new-onset pediatric IBD patients in 17 European countries and Israel. When a complete diagnostic workup was performed (ileocolonoscopy, upper gastrointestinal [GI] endoscopy, small bowel imaging), CD patients were evaluated for ileocolonic disease extent, esophagogastroduodenal involvement, and jejunal/proximal ileal involvement. Disease behavior and the occurrence of granulomas were also analyzed. RESULTS: In all, 582 pediatric CD patients could be classified according to the Paris classification. Isolated terminal ileal disease (± limited cecal disease) was seen at presentation in 16%, isolated colonic disease in 27%, ileocolonic disease in 53%, and isolated upper GI disease in 4% of patients. In total, 30% had esophagogastroduodenal involvement and 24% jejunal/proximal ileal disease. Patients with L2 disease were less likely to have esophagogastroduodenal involvement or stricturing disease than patients with L1 or L3 disease. Terminal ileal disease and stricturing disease behavior were more common in children diagnosed after 10 years of age than in younger patients. Granulomas were identified in 43% of patients. CONCLUSIONS: Accurate phenotyping is essential in pediatric CD, as this affects the management of individual patients. Disease phenotypes differ according to age at disease onset. The Paris classification is a useful tool to capture the variety of phenotypic characteristics of pediatric CD.

Percutaneous endoscopic colostomy of the left colon: a new technique for management of intractable constipation in children.

BACKGROUND: The antegrade colonic enema is accepted as effective for management of intractable constipation in children when conventional bowel management has failed. This study describes experience with a new, minimally invasive technique, the distal antegrade colonic enema, which involves percutaneous endoscopic colostomy of the left colon. METHODS: Fifteen children with refractory constipation and soiling who had radiographic evidence of megarectum and/or distal colonic delay were selected for the procedure. The junction of the descending and the sigmoid colon was identified colonoscopically, and the percutaneous endoscopic colostomy tube, through which antegrade distal colonic enema are administered, was inserted. RESULTS: Fourteen children underwent distal percutaneous endoscopic colostomy insertion. The median time required for the procedure was 30 minutes (20-50 minutes). Excluding one child (technical difficulties with percutaneous endoscopic colostomy placement), median post-procedural hospital stay was 4 days (2-27 days). Thirteen children were no longer soiling, and improvement in quality of life was reported at 2 months' follow-up. At 6 months' follow-up, 90% of children were clean during intervals between enemas. All children evaluated at 12 months' follow-up remained clean. Median duration of follow-up was 12.5 months (2-51 months). CONCLUSIONS: The distal percutaneous endoscopic colostomy is a simple alternative to established methods for delivery of antegrade enemas. It is less invasive and on reversal leaves only minor scarring.