Dominique Charles Belli

A proposition for the diagnosis and treatment of gastro-oesophageal reflux disease in children: A report from a working group on gastro-oesophageal reflux disease

In this paper, a Working Group on Gastro-Oesophageal Reflux discusses recommendations for the first line diagnostic and therapeutic approach of gastro-oesophageal reflux disease in infants and children. All members of the Working Group agreed that infants with uncomplicated gastro-oesophageal reflux can be safely treated before performing (expensive and often unnecessary) complementary investigations. However, the latter are mandatory if symptoms persist despite appropriate treatment. Oesophageal pH monitoring of long duration (18–24 h) is recommended as the investigation technique of choice in infants and children with atypical presentations of gastro-oesophageal reflux. Upper gastro-intestinal endoscopy in a specialised centre is the technique of choice in infants and children presenting with symptoms suggestive of peptic oesophagitis. Prokinetics, still a relatively new drug family, have already obtained a definitive place in the treatment of gastro-oesophageal reflux disease in infants and children, especially if “non-drug” treatment (positional therapy, dietary recommendations, etc.) was unsuccessful. It was the aim of the Working Group to help the paediatrician with this consensus statement and guide-lines to establish a standardised management of gastro-oesophageal reflux disease in infants and children.

Hyperinflammation in chronic granulomatous disease and anti-inflammatory role of the phagocyte NADPH oxidase.

Chronic granulomatous disease (CGD) is an immunodeficiency caused by the lack of the superoxide-producing phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. However, CGD patients not only suffer from recurrent infections, but also present with inflammatory, non-infectious conditions. Among the latter, granulomas figure prominently, which gave the name to the disease, and colitis, which is frequent and leads to a substantial morbidity. In this paper, we systematically review the inflammatory lesions in different organs of CGD patients and compare them to observations in CGD mouse models. In addition to the more classical inflammatory lesions, CGD patients and their relatives have increased frequency of autoimmune diseases, and CGD mice are arthritis-prone. Possible mechanisms involved in CGD hyperinflammation include decreased degradation of phagocytosed material, redox-dependent termination of proinflammatory mediators and/or signaling, as well as redox-dependent cross-talk between phagocytes and lymphocytes (e.g. defective tryptophan catabolism). As a conclusion from this review, we propose the existence of ROShigh and ROSlow inflammatory responses, which are triggered as a function of the level of reactive oxygen species and have specific characteristics in terms of physiology and pathophysiology.

Postoperative Chylothorax in Children: Differences Between Vascular and Traumatic Origin

Twenty-four children with postoperative chylothorax were encountered among 1,264 consecutive thoracic operations over a 7-year period and form the basis of this study. Chylothorax was caused by direct lesion to the thoracic duct or lymphatic vessels in 17 patients and was associated with superior vena cava (SVC) obstruction in seven. Of the latter, five had bilateral chylothorax. Chylothoraces secondary to venous hypertension and thrombosis have a longer interval between operation and diagnosis compared with direct trauma as well as a longer duration and larger volume of chylous drainage. Treatment was entirely nonoperative in 16 patients and operative in 8. Nonoperative treatment consisted of pleural needle aspiration or suction drainage in association with a medium chain triglyceride (MCT) diet (n = 11) or total parenteral nutrition (TPN) after failure of MCT (n = 5). Direct operation on the thoracic duct was performed in 5 patients, four had pleurodesis, and 2 had pleuroperitoneal shunts inserted. All patients were cured of their chylothorax and there were no deaths. Patients with major vein thrombosis were the most difficult to treat. On the basis of this experience, we suggest a step-by-step approach: (1) insertion of chest tube after 3 to 4 pleural punctures; (2) 1-week trial of MCT diet, with intravenous support to correct protein losses; (3) TPN if chylothorax increases or persists with large volumes; (4) Doppler echocardiography or phlebography to rule out obstruction of major thoracic veins; and (5) insertion of TPN line in inferior vena cava in case of such obstruction; and (6) direct surgical approach to the thoracic duct after 4 weeks of unsuccessful nonoperative treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

A critical appraisal of current management practices for infant regurgitation--recommendations of a working party.

Regurgitation is a common manifestation in infants below the age of 1 year and a frequent reason of counselling of general practitioners and paediatricians. Current management starts with postural and dietary measures, followed by antacids and prokinetics. Recent issues such as an increased risk of sudden infant death in the prone sleeping position and persistent occult gastro-oesophageal reflux in a subset of infants receiving milk thickeners or thickened “anti-regurgitation formula” challenge the established approach. Therefore, the clinical practices for management of infant regurgitation have been critically evaluated with respect to their efficacy, safety and practical implications. The updated recommendations reached by the working party on the management of infant regurgitation contain five phases: (1A) parental reassurance; (1B) milk-thick ening agents; (2) prokinetics; (3) positional therapy as an adjuvant therapy; (4A) H2-blockers; (4B) proton pump inhibitors; (5) surgery.

The role of cisapride in the treatment of pediatric gastroesophageal reflux. The European Society of Paediatric Gastroenterology, Hepatology and Nutrition.

BACKGROUND Cisapride is a gastrointestinal prokinetic agent that is used worldwide in the treatment of gastrointestinal motility-related disorders in premature infants, full-term infants, and children. Efficacy data suggest that it is the most effective commercially available prokinetic drug. METHODS Because of recent concerns about safety, a critical and in-depth analysis of all reported adverse events was performed and resulted in the conclusions and recommendations that follow. RESULTS Cisapride should only be administered to patients in whom the use of prokinetics is justified according to current medical knowledge. If cisapride is given to pediatric patients who can be considered healthy except for their gastrointestinal motility disorder, and the maximum dose does not exceed 0.8 mg/kg per day in 3 to 4 administrations of 0.2 mg/kg (not exceeding 40 mg/d), no special safety procedures regarding potential cardiac adverse events are recommended. However, if cisapride is prescribed for patients who are known to be or are suspected of being at increased risk for drug-associated increases in QTc interval, certain precautions are advisable. Such patients include those:(1) with a previous history of cardiac dysrhythmias, (2) receiving drugs known to inhibit the metabolism of cisapride and/or adversely affect ventricular repolarisation, (3) with immaturity and/or disease causing reduced cytochrome P450 3A4 activity, or (4) with electrolyte disturbances. In such patients, ECG monitoring to quantitate the QTc interval should be used before initiation of therapy and after 3 days of treatment to ascertain whether a cisapride-induced cardiac adverse effect is present. CONCLUSIONS With rare exceptions, the total daily dose of cisapride should not exceed 0.8 mg/kg divided into 3 or 4 approximately equally spaced doses. If higher doses than this are given, the precautions above are advisable. In any patient in whom a prolonged QTc interval is found, the dose of cisapride should be reduced or the drug discontinued until the ECG normalizes. If the QTc interval returns to normal after withdrawal of cisapride, and the administration of cisapride is considered to be justified because of its efficacy and absence of alternative treatment options, cisapride can be restarted at half dose with control of the QTc interval. Unfortunately, at present, normal ranges of QTc interval in children are unknown. However, a critical analysis of the literature suggests that a duration of less than 450 milliseconds can be considered to be within the normal range and greater than 470 milliseconds as outside it.

Biliary atresia: Swiss national study, 1994-2004

Objectives: To determine the epidemiology of biliary atresia (BA) in Switzerland, the outcome of the children from diagnosis, and the prognostic factors. Patients and Methods: The records of all patients with BA born in Switzerland between January 1994 and December 2004 were analyzed. Survival rates were calculated with the Kaplan-Meier method, and prognostic factors evaluated with the log rank test. Median follow up was 58 months (range, 5–124). Results: BA was diagnosed in 48 children. Incidence was 1 in 17,800 live births (95% confidence interval 1/13,900–1/24,800), without significant regional, annual, or seasonal variation. Forty-three children underwent a Kasai portoenterostomy (PE) in 5 different Swiss pediatric surgery units. Median age at Kasai PE was 68 days (range, 30–126). Four-year survival with native liver after Kasai PE was 37.4%. Liver transplantation (LT) was needed in 31 in 48 children with BA, including 5 patients without previous Kasai PE. Four patients (8%, all born before 2001) died while waiting for LT, and 29 LT were performed in 27 patients (28 in Geneva and 1 in Paris). All of the transplanted patients are alive. Four-year overall BA patient survival was 91.7%. Four-year survival with native liver was 75% in patients who underwent Kasai PE before 46 days, 33% in patients operated on between 46 and 75 days, and 11% in patients operated on after 75 days (P = 0.02). Conclusions: Overall survival of patients with BA in Switzerland compares favorably with current international standards, whereas results of the Kasai operation could be improved to reduce the need for LTs in infancy and early childhood.

Efficacy and tolerance of infliximab in children and adolescents with Crohn's disease.

Infliximab, a monoclonal antibody against tumor necrosis factor-alpha, has been shown to be effective for the treatment of refractory Crohn’s disease in adult patients, but experience in pediatrics is limited. This retrospective study included 88 children and adolescents, 39 girls and 49 boys, with a median age of 14 years (range 3.3–17.9). Infliximab was indicated for active disease (66%) and/or fistulas (42%) that were refractory to corticosteroids (70%), and/or other immunosuppressive (82%) agents, and/or parenteral nutrition (20%). Patients received 1 to 17 infusions (median 4) of 5 mg/kg (range 3.8–7.3) of infliximab during a median time period of 4 months (1–17 months). Infusion reaction was noted in 13 patients (15%), with a total of 16 reactions in 450 infusions (4%). At Day 90 after the first infusion of infliximab, symptoms improved in 49% of patients, whereas 29% of patients were in remission and 13% of patients relapsed. From Day 0 to Day 90, Harvey–Bradshaw score decreased from 7.5 to 2.8 (P < 0.001), C-reactive protein from 36 to 16 mg/L (P < 0.01), and 1-hour erythrocyte sedimentation rate from 35 to 17 mm (P < 0.01). Dosage of corticosteroids decreased from to 0.59 to 0.17 mg/kg/d (P < 0.001); 53% of patients could be weaned of corticosteroids and 92% of parenteral nutrition. Treatment with infliximab is well tolerated and effective in most children and adolescents with Crohn’s disease that is refractory to conventional immunosuppressive therapy. Nevertheless, long-term efficacy remains to be shown, and further studies are urgently needed to precisely determine the best modality of continuing treatment.

Current concepts and issues in the management of regurgitation of infants: A reappraisal

Regurgitation in infants is a common problem. Recent issues, such as the increased risk of sudden infant death in the prone sleeping position, the finding of persisting occult gastro‐oesophageal reflux with feed thickeners, and the increasing awareness of the cost‐benefit ratio of medications may challenge the currently recommended management approach. A round table was organized to elaborate on the impact of (i) the pro supine sleeping campaigns in relation to sudden infant death and (ii) advancement in medical treatment on therapeutic strategies in regurgitating infants. The participants were opinion leaders from Europe and North America (Belgium, Canada, France, UK, Italy, Switzerland and The Netherlands). The importance of parental reassurance is stressed. As a consequence of the supine sleeping campaigns aiming to decrease the incidence of sudden infant death syndrome, the “prone elevated sleeping position” is no longer advised as a first‐line therapeutic approach, although it is still recommended in “complicated reflux”. It is emphasized that milk thickeners are an adequate therapeutic tool for regurgitation, but not in reflux disease. According to the literature, the efficacy of (alginate‐) antacids, although very popular in some countries, is questionable. These recommendations will be of interest to first‐line paediatricians, since about 40% of their patients, according to the literature, present because of regurgitation.

Varicella‐Zoster Immunization in Pediatric Liver Transplant Recipients: Safe and Immunogenic

Varicella can have a severe course in immunosuppressed patients. Although prevention is fundamental, live‐attenuated varicella‐zoster (VZV) vaccine is not currently recommended in transplant recipients. Our aims were to (1) evaluate VZV immunity in pediatric liver transplant (LT) recipients; (2) immunize (two doses) seronegative patients post‐LT; (3) monitor vaccine safety, (4) assess B and T cell vaccine responses. All patients followed at the Swiss National Pediatric LT Center were approached and 77/79 (97.5%) were enrolled (median age 7.8 years). Vaccine safety was monitored by standardized diary cards and phone calls. VZV‐specific serology and CD4+ T cells were assessed before and after immunization. Thirty‐nine patients (51.1%) were seronegative including 14 children immunized pre‐LT. Thirty‐six of 39 seronegative patients were immunized post‐LT (median 3.0 years post LT). Local (54.8%) and systemic (64.5%) reactions were mild and transient. The frequency of VZV‐specific CD4+ T cells and antibody titers increased significantly (respectively from 0.085% to 0.16%, p = 0.04 and 21.0 to 1134.5 IU/L, p < 0.001). All children reached seroprotective titers and 31/32 (97%) patients assessed remained seroprotected at follow‐up (median 1.7 years). No breakthrough disease was reported during follow‐up (median 4.1 years). Thereby, VZV vaccine appears to be safe, immunogenic and provide protection against disease in pediatric LT patients.

Food poisoning as a cause of acute liver failure.

We report a 9-year-old girl with cereulide-producing Bacillus cereus food poisoning, who developed fulminant hepatitis, renal and pancreatic insufficiency, shock, and prolonged seizures. She was transferred to our institution for hepatic transplantation before her diagnosis was established. As a result of rapid identification of the microorganism and supportive care, liver transplantation was avoided, and she recovered fully.