An ESPGHAN Position Paper on the Use of Low-FODMAP Diet in Pediatric Gastroenterology.

Excluding oligo-, di-, monosaccharides and polyols (FODMAPs) from the diet is increasingly being used to treat children with gastrointestinal complaints. The aim of this position paper is to review the available evidence on the safety and efficacy of its use in children and provide expert guidance regarding practical aspects in case its use is considered . Members of the Gastroenterology Committee, the Nutrition Committee and the Allied Health Professionals Committee of the European Society for Pediatric Gastroenterology Hepatology and Nutrition contributed to this position paper. Clinical questions regarding initiation, introduction, duration, weaning, monitoring, professional guidance, safety and risks of the diet are addressed. A systematic literature search was performed from 2005 to May 2021 using PubMed, MEDLINE and Cochrane Database of Systematic Reviews. In the absence of evidence, recommendations reflect the expert opinion of the authors. The systematic literature search revealed that the low-FODMAP diet has not been comprehensively studied in children. Indications and contraindications of the use of the diet in different pediatric gastroenterological conditions are discussed and practical recommendations are formulated. There is scarce evidence to support the use of a low-FODMAP diet in children with Irritable Bowel Syndrome and no evidence to recommend its use in other gastrointestinal diseases and complaints in children. Awareness of how and when to use the diet is crucial, as a restrictive diet may impact nutritional adequacy and/or promote distorted eating in vulnerable subjects. The present article provides practical safety tips to be applied when the low-FODMAP diet is considered in children.

What is the best method for calculating the optimal position of an esophageal pH probe in children?

In assessment of distal esophageal pH, the sensor of the probe should be placed above the upper border of the lower esophageal sphincter. There are several methods to estimate the distance from the nose where the probe should be fixed according to the patient's height. We studied the accuracy of these methods. Data of patients who underwent esophageal monitoring were collected prospectively. The esophageal pH electrode was set with the aid of fluoroscopy in all cases, considering the location recommended by the current guideline. Esophageal probe position and anthropometric data of each patient were recorded. We compared the actual esophageal pH electrode distance from the nose with that estimated by Nowak's, Strobel's, Staiano-Clouse's, and Moreau's formulae and the Great Ormond Street Hospital (GOSH) table. A total of 98 patients were included, with ages ranging from 2 months to 19 years old. The highest success rate (67%) for all age groups was achieved by Nowak's formula (3.2 + 0.2 × height in cm). Considering only children under 3 years old, the GOSH table reached the highest-yet probably overestimated-fraction of adequate predictions. A corrected Staiano and Clouse's formula (4.28 + 0.191 × height in cm) had a slightly lower success rate than Nowak's due to a poorer performance in younger children. In conclusion, Nowak's formula is the most accurate regardless of age. It can help reduce radiation due to systematic fluoroscopy, as well as the subsequent manipulation of the esophageal probe. However, it still leads to pH sensor misplacements in more than one-third of children. In consequence, a confirmatory X-ray is advisable even after using the formula.

A systematic review with meta-analysis of the prevalence of gastroesophageal reflux in congenital diaphragmatic hernia pediatric survivors.

Congenital diaphragmatic hernia survivors are a well-known group at risk for developing gastroesophageal reflux disease that may be particularly long-term severe. The aim of this study is to provide a systematic review of the prevalence of gastroesophageal reflux in infant and children survivors treated for congenital diaphragmatic hernia.Electronic and manual searches were performed with keywords related to congenital diaphragmatic hernia, gastroesophageal reflux disease, and epidemiology terms. Summary estimates of the prevalence were calculated. Effect model was chosen depending on heterogeneity (I2). Factors potentially related with the prevalence, including study quality or the diagnostic strategy followed, were assessed by subgroup and meta-regression analyses. Risk of publication bias was studied by funnel plot analysis and the Egger test.The search yielded 140 articles, 26 of which were included in the analyses and provided 34 estimates of prevalence: 21 in patients aged 12 months or younger, and 13 in older children. The overall prevalence of gastroesophageal reflux disease in infants was 52.7% (95% confidence interval [CI]: 43.2% to 62.1%, I2 = 88.7%) and, in children over 1 year old, 35.1% (95% CI: 25.4% to 45.3%, I2 = 73.5%). Significant clinical and statistical heterogeneity was found. The strategy chosen for gastroesophageal reflux diagnosis influenced the reported prevalence. The only estimate obtained with a systematic use of multichannel intraluminal impedance provided a higher prevalence in both age groups: 83.3% (95% CI: 67.2% to 93.6%) and 61.1% (95% CI: 43.5% to 76.9%) respectively. This last prevalence did not significantly differ from that obtained using only low risk of bias estimates.As a conclusion, gastroesophageal reflux disease is commonly observed after congenital diaphragmatic hernia repair and is almost constantly present in the first months of life. It may be underdiagnosed if systematically esophageal monitoring is not performed. This should be considered when proposing follow-up and management protocols for congenital diaphragmatic hernia survivors.

A pilot study of the use of the oral and faecal microbiota for the diagnosis of ulcerative colitis and Crohn's disease in a paediatric population.

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) that affect the gastrointestinal tract. Changes in the microbiome and its interaction with the immune system are thought to play a key role in their development. The aim of this study was to determine whether metagenomic analysis is a feasible non-invasive diagnostic tool for IBD in paediatric patients. A pilot study of oral and faecal microbiota was proposed with 36 paediatric patients divided in three cohorts [12 with CD, 12 with UC and 12 healthy controls (HC)] with 6 months of follow-up. Finally, 30 participants were included: 13 with CD, 11 with UC and 8 HC (6 dropped out during follow-up). Despite the small size of the study population, a differential pattern of microbial biodiversity was observed between IBD patients and the control group. Twenty-one bacterial species were selected in function of their discriminant accuracy, forming three sets of potential markers of IBD. Although IBD diagnosis requires comprehensive medical evaluation, the findings of this study show that faecal metagenomics or a reduced set of bacterial markers could be useful as a non-invasive tool for an easier and earlier diagnosis.

[Response to stopping azathioprine in Crohn's patients on combined treatment with infliximab]. / Respuesta a la suspensión de azatioprina en pacientes con enfermedad de Crohn en terapia combinada con infliximab.

BACKGROUND: The use of immunomodulatory agents has changed the management of inflammatory bowel disease. Immunosuppressive drugs (mainly thiopurines) and biological treatments (mainly monoclonal antibodies against TNFalpha) are currently most frequently and earlier used. The recent report of new cases of the rare and almost always fatal hepatosplenic T-cell lymphoma in young patients on combined therapy with azathioprine/6-mercaptopurine and infliximab suggests that the optimal strategies for reducing increased risk of side-effects need to be urgently assessed. PATIENTS AND METHOD: We report the effects of stopping immunosupressants in four Crohn's disease patients previously treated with azathioprine and infliximab for 6-12 months as combined therapy. The appearance of infusion reactions due to immunogenicity and the loss of efficacy of infliximab are evaluated. RESULTS: No adverse events attributable to immunosuppression cessation or changes in infliximab efficacy have been noted during a 6-month evaluation period. CONCLUSIONS: Stopping immunosuppressant therapy in Crohn's patients with a previous good response to combination therapy (azathioprine and infliximab) does not result in an increased risk of adverse events or loss of infliximab efficacy. Our results must be confirmed in larger and longer studies. Until the pathogenic role of this combined therapy in the incidence of hepatosplenic T-cell lymphoma is clearly defined, we consider that monotherapy with infliximab after a period on combined treatment is a safe and effective strategy.

[Progressive familial intrahepatic cholestasis presenting as liver failure]. / Fallo hepático neonatal como forma de presentación de colestasis intrahepática familiar progresiva.

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomic-recessive inherited cholestatic disorders that begin in the neonatal period or in the first years of life. There are three types of PFIC defined by different mutations located in the gene responsible for the bile flow through the intrahepatic canalicular transporter system. These disorders usually present in children or young adults and the main clinical manifestations are cholestasis, jaundice and pruritus, and they progress slowly towards liver fibrosis in adult life. PFIC diagnosis is based on clinical suspicion, biochemical findings (that include normal gamma-glutamyl transpeptidase in type 1 and 2, but increased levels in type 3), image techniques that rule-out other disorders, and histological confirmation. Initial treatment consists of symptomatic relief of cholestatic symptoms with choleretic agents (urso-deoxycholic acid). Partial biliary derivation and ileal bypass are intermediate therapeutic options. In case of no response to these treatments, liver transplantation is indicated. We report the case of a neonate with PFIC type 2 presenting as a liver failure.

[Skin manifestations of pediatric inflammatory bowel disease]. / Manifestaciones cutáneas de la enfermedad inflamatoria intestinal.

Skin manifestations have been described in 10-15% of patients with inflammatory bowel disease (Crohn's disease, ulcerative colitis, indeterminate colitis/inflammatory bowel disease type unclassified). There are limited data on the prevalence of these manifestations in paediatric patients, but recent studies have reported its presence in 8% of them at diagnosis. Our aim is to report the different skin manifestations observed in our paediatric patients with inflammatory bowel disease. Case 1: Erythema nodosum at Crohn's disease diagnosis. Typical presentation with painful erythematous nodules in the pretibial region and with good response to infliximab. Case 2: Coexistence of pyoderma gangrenosum and mucocutaneous Sweet's syndrome in a Crohn's disease patient. A rapidly progressive disease that was controlled with systemic steroids but with significant residual lesions. Case 3 and 4: Metastatic Crohn's disease with good response to infliximab.

[Infliximab as rescue therapy in severe steroid-resistant ulcerative colitis]. / Infliximab como terapia de rescate en colitis ulcerosa grave resistente al tratamiento corticoideo.

Paediatric ulcerative colitis tends to be more severe and more extensive than in adults. Steroid-resistance is also more frequent, producing a high colectomy rate in these patients. Cyclosporine A has showed to be an effective rescue therapy in acute attacks, avoiding colectomy. However, the long-term benefits are less promising and there is also very serious toxicity associated with its use. Therefore, novel effective therapies in paediatric ulcerative colitis are mandatory. We present a patient with a severe attack of steroid-resistant ulcerative-colitis in whom infliximab has proved effective in inducing a maintained remission and in avoiding the need for colectomy.

Malignancy and mortality in paediatric-onset inflammatory bowel disease: a 3-year prospective, multinational study from the paediatric IBD Porto group of ESPGHAN.

BACKGROUND: Risk benefit strategies in managing inflammatory bowel diseases (IBD) are dependent upon understanding the risks of uncontrolled inflammation vs those of treatments. Malignancy and mortality in IBD have been associated with disease-related inflammation and immune suppression, but data are limited due to their rare occurrence. AIM: To identify and describe the most common causes of mortality, types of cancer and previous or current therapy among children and young adults with paediatric-onset IBD. METHODS: Information on paediatric-onset IBD patients diagnosed with malignancy or mortality was prospectively collected via a survey in 25 countries over a 42-month period. Patients were included if death or malignancy occurred after IBD diagnosis but before the age of 26 years. RESULTS: In total, 60 patients were identified including 43 malignancies and 26 fatal cases (9 due to cancer). Main causes of fatality were malignancies (n = 9), IBD or IBD-therapy related nonmalignant causes (n = 10; including 5 infections), and suicides (n = 3). Three cases, all fatal, of hepatosplenic T-cell lymphoma were identified, all were biologic-naïve but thiopurine-exposed. No other haematological malignancies were fatal. The 6 other fatal cancer cases included 3 colorectal adenocarcinomas and 3 cholangiocarcinomas (CCAs). Primary sclerosing cholangitis (PSC) was present in 5 (56%) fatal cancers (1 colorectal carcinoma, 3 CCAs and 1 hepatosplenic T-cell lymphoma). CONCLUSIONS: We report the largest number of paediatric-onset IBD patients with cancer and/or fatal outcomes to date. Malignancies followed by infections were the major causes of mortality. We identified PSC as a significant risk factor for cancer-associated mortality. Disease-related adenocarcinomas were a commoner cause of death than lymphomas.

[Autoimmune hepatitis in pediatric patients]. / Hepatitis autoinmune en la edad pediátrica.

BACKGROUND: Autoimmune hepatitis (AIH) is an inflammatory disease of unknown origin that is responsible for progressive liver necrosis and ultimately cirrhosis. OBJECTIVE: Our aim was to evaluate the characteristics of autoimmune hepatitis presenting in the pediatric age. MATERIAL AND METHODS: We conducted a retrospective study of all patients diagnosed with AIH in our hospital department during the last 10 years. Variables analyzed included age, sex, clinical presentation, hepatic function, immunoglobulins, autoimmunity markers, histology, treatment, need for transplant, and clinical evolution. According to the positive level of auto-antibodies, AIH patients were classified as type I AIH (ANA and/or smooth-muscle antibodies) and type II (anti-LKM-1). RESULTS: Seven patients were diagnosed in this period -5 girls (71.5%) and 2 boys (28.5%). Five patients presented with type-I serological markers, and two with type-II markers. Age range at diagnosis was from 21 months to 12 years. In the type-I group, 3 patients presented with acute hepatitis while 2 other patients were diagnosed from laboratory findings while asymptomatic. Elevated aminotransferase (10 times the normal level) was observed in 71.5%, and 85% had elevated immunoglobulins. Treatment with azathioprine and prednisone was started after diagnosis with an average time to remission of 14 months. Two patients relapsed following steroid withdrawal. CONCLUSION: AIH can have different forms of clinical presentation, and is sometimes indistinguishable from viral hepatitis. AIH must be ruled out in patients presenting with concomitant elevation of aminotransferases and immunoglobulins. The commonly accepted treatment is a combination of azathioprine and corticosteroids. A high percentage of patients experience a relapse of disease after steroids are withdrawn. Therefore, some patients will need to stay on combined therapy with minimal doses of steroids.

[Increasing diagnosis of eosinophilic esophagitis in Spain]. / Aumento del diagnóstico de esofagitis eosinofílica en nuestro medio.

INTRODUCTION: Eosinophilic esophagitis is a chronic inflammation of the esophagus characterized by marked eosinophilic infiltration. It is frequently associated with other allergic diseases. In the last few years, the incidence of eosinophilic infiltration has shown a striking increase in Spain, partly due to better knowledge of the disease and to the correct diagnosis of patients previously thought to be suffering from gastroesophageal reflux. MATERIAL AND METHODS: To report our experience in the diagnosis of eosinophilic esophagitis in the last few years and compare our data with previously published findings and current knowledge of the subject. RESULTS: From January 1997 to November 2003, 11 patients (nine boys and two girls) were diagnosed with eosinophilic esophagitis. The mean age at diagnosis was 9 years and 7 months. The most frequent symptoms were dysphagia with solids and food impaction. Seven patients had a familial history of allergy. Allergic tests were positive in eight patients; five had food allergy, five were positive for aeroallergens and two patients had mixed allergy. Endoscopy showed esophageal trachealization in two patients and papular whitish exudate in a further two; both these findings are characteristic of eosinophilic esophagitis. Endoscopic appearance was normal in seven patients. Esophageal biopsies showed > 20 eosinophils/hpf. Five patients had eosinophilic infiltration in other parts of the digestive tract. All the patients with food allergy were put on exclusion diets. Three patients received systemic steroids and cromolyn sodium and three received montelukast, with good response in all patients. CONCLUSIONS: The incidence of eosinophilic esophagitis is increasing. This disease should be considered in patients with longstanding symptoms presumed to be caused by gastroesophageal reflux or motility disorders with poor response to standard therapy. Eosinophilic esophagitis is frequently associated with allergy. A normal appearance of esophageal mucosa on endoscopy should not prevent the clinician from taking multiple biopsies. Patients with eosinophilic esophagitis show good response to anti-allergic treatment.

[Neonatal hemochromatosis: Another entity that is no longer orphan. Advances in the diagnosis and management of the main cause of neonatal acute liver failure]. / Hemocromatosis neonatal: otra entidad que deja de ser huérfana. Avances en el diagnóstico y manejo de la principal causa de fallo hepático agudo neonatal.

Neonatal hemochromatosis is the most common cause of acute liver failure in the neonatal period. It is associated with high morbidity and mortality due to iron overload in hepatic and extra-hepatic tissues. New evidence has emerged during the last few years as regards its alloimmune etiology, which have had an important repercussion on the diagnosis, treatment and prognosis of these patients. Treatment with immunoglobulins and exchange transfusions has radically changed the prognosis without liver transplant. Another great success has been the preventive use of immunoglobulin in pregnant women with a past history of neonatal hemochromatosis, thus decreasing the rate of disease recurrence up to 70%. This new paradigm has led to an entity with a poor prognosis becoming a curable disease if diagnosed and treated early. Nevertheless, a large widespread ignorance of the disease persists, with medical implications that result in significant health problems, due to the delayed referral of these patients to specialized centers.

[Ulcerative colitis associated with autoimmune hepatitis: a differential form of inflammatory bowel disease?]. / Colitis ulcerosa asociada a hepatitis autoinmune: ¿una forma diferencial de enfermedad inflamatoria intestinal?

Inflammatory bowel Disease (IBD) is a group of chronic inflammatory diseases that can be associated with different autoimmune diseases, including autoimmune hepatitis (AIH). Some specific and differential characteristics in children with IBD associated to AIH have been described. Our aim is to describe the clinical pattern of this association observed in our patients, confirming its differential characteristics as compared to classical IBD in children.

The complete picture of changing pediatric inflammatory bowel disease incidence in Spain in 25 years (1985-2009): the EXPERIENCE registry.

OBJECTIVES: A growing incidence of pediatric IBD (PIBD) in southern Europe has been recently reported. The SPIRIT registry (1996-2009) confirmed these tendencies in Spain. Our aim is to obtain data from 1985 to 1995 and describe the complete picture of PIBD presentation changes in Spain in the last 25years. METHODS: A retrospective survey of incident PIBD in the period 1985-1995 was performed. Patients' data were obtained from the hospitals' databases and compared with the published data from the 1996 to 2009 period. Seventy-eight IBD reference centers took part in this survey. RESULTS: Data from 495 patients were obtained: 278 CD (56.2%), 198 UC (40%), and 19 IBDU (3.8%); 51.7% were female, with higher predominance both in UC (58.6%) and in IBDU (57.9%), but not in CD (46.4%). Median (IQR) age at diagnosis was 12.9 (10.0-15.7) years, with significant differences among IBD subtypes: CD: 13.1 (10.8-16.0) vs UC: 12.4 (9.4-15.1) vs IBDU: 7.5 (3.0-13.0) (p≤0.001). These results are significantly different to the ones in the SPIRIT registry, with a higher proportion of IBDU, younger age and male predominance. The data from both periods taken together give a complete picture of a 25-year period. An annual increase of incident patients was observed, with a ten-fold increase over this period. CONCLUSION: These data extend the epidemiological trends to a full 25-year period (1985-2009). PIBD incidence in Spain has experienced a sixteen-fold increase. The IBD subtype, localization of the affected segment, age- and sex distribution observed are in accordance with our previously published ones of 1996-2009.

Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease.

Children and adolescents with Crohn's disease (CD) present often with a more complicated disease course compared to adult patients. In addition, the potential impact of CD on growth, pubertal and emotional development of patients underlines the need for a specific management strategy of pediatric-onset CD. To develop the first evidenced based and consensus driven guidelines for pediatric-onset CD an expert panel of 33 IBD specialists was formed after an open call within the European Crohn's and Colitis Organisation and the European Society of Pediatric Gastroenterolog, Hepatology and Nutrition. The aim was to base on a thorough review of existing evidence a state of the art guidance on the medical treatment and long term management of children and adolescents with CD, with individualized treatment algorithms based on a benefit-risk analysis according to different clinical scenarios. In children and adolescents who did not have finished their growth, exclusive enteral nutrition (EEN) is the induction therapy of first choice due to its excellent safety profile, preferable over corticosteroids, which are equipotential to induce remission. The majority of patients with pediatric-onset CD require immunomodulator based maintenance therapy. The experts discuss several factors potentially predictive for poor disease outcome (such as severe perianal fistulizing disease, severe stricturing/penetrating disease, severe growth retardation, panenteric disease, persistent severe disease despite adequate induction therapy), which may incite to an anti-TNF-based top down approach. These guidelines are intended to give practical (whenever possible evidence-based) answers to (pediatric) gastroenterologists who take care of children and adolescents with CD; they are not meant to be a rule or legal standard, since many different clinical scenario exist requiring treatment strategies not covered by or different from these guidelines.