[New therapeutic developments in cystic fibrosis]. / Nouvelles thérapeutiques ciblant le canal chlorure dans la mucoviscidose.

Since the discovery of chloride secretion by the Cystic Fibrosis Transport regulator CFTR in 1983, and CFTR gene in 1989, knowledge about CFTR synthesis, maturation, intracellular transfer and function has dramatically expanded. These discoveries have led to the distribution of CF mutations into 6 classes with different pathophysiological mechanisms. In this article we will explore the state of art on CFTR synthesis and its chloride secretion function. We will then explore the consequences of the 6 classes of mutations on CFTR protein function and we will describe the new therapeutic developments aiming at correcting these defects.

[Malnutrition screening in clinical practice]. / Dépister la dénutrition de l'enfant en pratique courante.

Protein energy malnutrition (PEM) occurs when energy and protein intake do not meet requirements. It has a functional and structural impact and increases both morbidity and mortality of a given disease. The Nutrition Committee of the French Pediatric Society recommends weighing and measuring any child when hospitalized or seen in consultation. The body mass index (BMI) must be calculated and analyzed according to references any time growth kinetics cannot be analyzed. Any child with a BMI below the third centile or -2 standard deviations for age and sex needs to be examined looking for clinical signs of malnutrition and signs orienting toward an etiology and requires having his BMI and height dynamics plotted on a chart. PEM warrants drawing up a nutritional strategy along with the overall care plan. A target weight needs to be determined as well as the quantitative and qualitative nutritional care including its implementation. This plan must be evaluated afterwards in order to adapt the nutritional therapy.

Nutritional outcome in children with severe generalized recessive dystrophic epidermolysis bullosa: a short- and long-term evaluation of gastrostomy and enteral feeding.

BACKGROUND: Generalized recessive dystrophic epidermolysis bullosa (RDEB) is often complicated by high nutritional difficulties with risks of malnutrition. OBJECTIVES: To provide information regarding the benefits of enteral feeding by gastrostomy (GTF), energy and protein requirements, tolerance, growth and pubertal development in children with RDEB. METHODS: Twenty-four patients were referred over a 7-year period in a retrospective study. Gastrostomy placement was decided in patients unable to feed orally and/or presenting loss in weight and height of at least 1 SD compared with their best growth level, despite regular nutritional advice. Weight and height were expressed as Z-scores. Catch-up growth following GTF onset was studied. RESULTS: Gastrostomies were performed in 11 children (aged 9·0±5·8years), and one young man aged 18years. The body weight Z-score was -2·3±1·0, height Z-score 1·1±1·1, weight-for-height was 81±11% and height-for-age 95± 4%. At onset, GTF provided 74±21% and 180±81% of the recommended dietary allowance (RDA) for energy and proteins, respectively. At study update (53±20months), GTF provided 91±29% and 205±100% of RDA for energy and proteins, respectively. Weight-for-height reached 92±15% and height-for-age 98±5%. A normal puberty was obtained when GT was performed before the age of 10years. Skin was not improved. CONCLUSION: Malnutrition was observed in 50% of the children with generalized RDEB. Protein and energy needs are particularly high. GTF is well tolerated and helps with catch-up growth and puberty. It must be considered before malnutrition onset, and, if necessary, before puberty.

Is intestinal transplantation the future of children with definitive intestinal insufficiency?

UNLABELLED: Intestinal transplantation (IT) is the newest and most difficult of organ transplantations. The first ever (1987) and the longest surviving (1989) IT were performed in our institution. However, IT still has to demonstrate its benefit to children on long-term parenteral nutrition (PN). We tried to clarify this aspect by looking back at our 13 years' experience. PATIENTS: From 1994 to December 2007, 74 IT were performed in 69 children, 39 with an isolated small bowel (IT), 35 combined with a liver transplant (LITx). The indications were: short bowel syndrome (n = 25), congenital mucosal diseases (n = 22), and motility disorders (n = 22). Median age at transplantation was 5 years (1 - 17 years). Follow-up was 1 to 12 years (median 5 years). RESULTS: Thirty-one children have a functioning graft (42 %), 15/39 IT, 16/35 LITx. They are at home without PN, with a good quality of life. One child is PN-dependent 1.5 years post IT. Post IT, 16 children were detransplanted: 12 early on (1 for mechanical complications, 11 because of resistant rejection; 3 less than 3 years, one 9 years post SBT (chronic rejection). In 2 noncompliant teenagers, PN was reintroduced (one was detransplanted later on). Several years post LITx, 2 children underwent bowel detransplantation due to an acute viral infection complicated with rejection. Twenty-two children died (32 %, 8 IT, 14 LITx), 18 early on from infectious or surgical complications, 4 more than 1 year post IT, 3 after retransplantation (1 in another unit). Bad prognostic factors are multiple previous surgeries, an older age (> 7 y), and chronic intestinal pseudo-obstruction. DISCUSSION: Complications post IT are frequent and life-threatening, especially early on: rejection (IT), infections (LITx). Later on, the rate of complications decreases but remains significant, especially in noncompliant patients. However we describe here a 13-year learning curve; the recent results are encouraging with regard to control of rejection and viral infections. CONCLUSION: Intestinal transplantation is indicated only in selected patients in whom long-term PN cannot be performed safely any more. In every child with intestinal insufficiency, the therapeutic strategy must be discussed early on in order to perform IT at the right time under optimal conditions. IT should evolve from being a "rescue" procedure to becoming a true therapeutic option.

Long-term outcome, growth and digestive function in children 2 to 18 years after intestinal transplantation.

OBJECTIVE: Small bowel (SB) transplantation (Tx), long considered a rescue therapy for patients with intestinal failure, is now a well recognised alternative treatment strategy to parental nutrition (PN). In this retrospective study, we analysed graft functions in 31 children after SBTx with a follow-up of 2-18 years (median 7 years). PATIENTS: Twelve children had isolated SBTx, 19 had combined liver-SBTx and 17 received an additional colon graft. Growth, nutritional markers, stool balance studies, endoscopy and graft histology were recorded every 2-3 years post-Tx. RESULTS: All children were weaned from PN after Tx and 26 children remained PN-free. Enteral nutrition was required for 14/31 (45%) patients at 2 years post-Tx. All children had high dietary energy intakes. The degree of steatorrhoea was fairly constant, with fat and energy absorption rates of 84-89%. Growth parameters revealed at transplantation a mean height Z-score of -1.17. After Tx, two-thirds of children had normal growth, whereas in one-third, Z-scores remained lower than -2, concomitant to a delayed puberty. Adult height was normal in 5/6. Endoscopy and histology analyses were normal in asymptomatic patients. Chronic rejection occurred only in non-compliant patients. Five intestinal grafts were removed 2.5-8 years post-Tx for acute or chronic rejection. CONCLUSIONS: This series indicates that long-term intestinal autonomy for up to 18 years is possible in the majority of patients after SBTx. Subnormal energy absorption and moderate steatorrhoea were often compensated for by hyperphagia, allowing normal growth and attainment of adult height. Long-term compliance is an important pre-requisite for long-term graft function.

Factors influencing outcome after intestinal transplantation in children.

We evaluated 131 patients (6 months-14 years) who experienced 21 deaths before listing, 11 continuing on the waiting list, 38 well on home parenteral nutrition, 6 off parenteral nutrition and 59 transplanted (20 girls) aged 2.5 to 15 years, (18 >7 years). They received cadaveric isolated intestine (ITx, n = 31) or liver-small bowel (LITx, n = 32), including right colon (n = 43; 23 LITx) for short bowel (n = 19), enteropathy (n = 20), Hirschsprung (n = 14), or pseudo-obstruction (n = 6). Treatment included tacrolimus, steroids, azathioprine, or interleukin-2 blockers. After 6 months to 10.5 years, the patient and graft survivals were 75% and 54%. Sixteen patients (10 LITx) died within 3 months from surgery (n = 3), bacterial (n = 5) or fungal (n = 6) sepsis, or posttransplant lymphoproliferative disorder (n = 2). Rejection occurred in 27 patients, including 10 steroid-resistant episodes requiring antilymphoglobulins. The grafts were removed due to uncontrolled rejection in seven ITx recipients. Surgical complications were observed in 38 recipients (25 LSBTx) within 2 months, including bacterial (n = 22) or fungal (n = 11) sepsis, cytomegalovirus disease (n=12), adenovirus (n = 11), or posttransplant lymphoproliferative disorder (n = 12). Forty-two children (19 LSBTx) are alive. Weaning from parenteral nutrition was achieved after 42 days (median). Factors related to death or graft loss were pre-Tx surgery (P < .01), pseudo-obstruction (P < .01), age over 7 years (P < .03), fungal sepsis (P < .03), steroid resistant rejection (P < .05), hospitalized versus home patient (P < .01), and retransplantation (P < .05). Colon transplant did not affect the outcome. Interleukin-2 blockers improved isolated ITx (P < .05). Early referral and close monitoring of intestinal failure and related disorders are mandatory to achieve successful ITx.

Outcome and long-term growth after extensive small bowel resection in the neonatal period: a survey of 87 children.

UNLABELLED: This retrospective study aims to analyze the outcome, the prognosis factors and the long-term growth of children after extensive small bowel (SB) resection in the neonatal period. PATIENTS AND METHODS: 87 children, born between 1975 and 1991 who had undergone extensive neonatal small bowel resection, were followed up over a mean period of 15 years. Anatomical data influencing PN dependency and duration were analyzed. Data on height and weight were collected and compared using growth standards. Final heights were studied for patients who achieved their puberty and compared to predicted height based on Tanner's formula. Patients were analyzed according to PN weaning and growth: children still receiving PN (group A), patients weaned from initial PN but requiring PN once again or enteral feeding (group B), and children with permanent intestinal autonomy (group C). RESULTS: The overall survival is 89.7 %, depending on the date of birth. The duration of PN-dependency varies according to the intestinal length and the presence of the ileocaecal valve (ICV). All patients who remain PN dependent had less than 40 cm of small bowel and/or the absence of ICV. Patients in group B had a mean small bowel length of 35 +/- 19 cm, resection of the ICV in 50 % of cases, and a PN duration of 47.4 +/- 23.8 months. There was a significant decrease in height and weight gain within the 4 years after cessation of PN, requiring enteral or parenteral feeding. Patients in group C had a mean small bowel length of 57 +/- 19 cm, presence of ICV in 81 % of cases and a PN duration of 16.1 +/- 11.4 months. After PN weaning, they grow up normally with normal puberty and final height as predicted from genetic target height. CONCLUSION: PN duration is influenced by the length of residual SB and the absence of ICV. With good anatomic prognosis factors and short duration of initial PN, normal long-term growth may be predicted. Conversely, poor anatomical factors and protracted initial PN require careful monitoring of growth and may sometimes require nutritional support to be restarted. The last group, permanently dependent on PN, might be candidates for intestinal transplantation.

Strategies for the diagnosis and treatment of bacteraemia in children with central venous catheters: an analysis.

The aim of this study was to analyse the diagnostic, empirical and therapeutic strategies adopted when a blood culture from a hospitalized child with a central venous catheter is 'positive', and to assess whether practices complied with the consensus adopted in our hospital, inspired by published recommendations. One hundred and ten cases of bacteraemia were studied prospectively. Investigations to determine whether the catheter was the cause of infection were carried out in 45% of cases, and the catheter was removed as recommended in 39% of cases. Of the patients that received empirical treatment, 56% received broad-spectrum antibiotics with no apparent clinical justification. Following susceptibility testing on the isolated strain, the antibiotic treatment was considered to be appropriate in 58% of cases. Overall, compliance with the consensus recommendations was poor. This was partly due to the high turnover rate of antibiotic prescribers.

Insulin-like growth factor I correlates with lean body mass in cystic fibrosis patients.

BACKGROUND: A major consequence of malnutrition in cystic fibrosis (CF) patients is the loss of lean body mass (LBM) and the subsequent impairment of respiratory muscle function. AIM: To determine whether insulin-like growth factor I (IGF-I) could be related to the LBM depletion and the evolution of respiratory disease in CF patients. METHODS: LBM was evaluated by dual energy x ray absorptiometry; serum concentrations of IGF-I were measured in 24 CF patients twice with a one year interval. Both values were expressed as SD score (SDS) calculated from normal data for age, sex, and pubertal stage and analysed with respect to anthropometric evaluation and disease related conditions. RESULTS: At the initial evaluation, IGF-I SDS had a mean value of -0.98 (range -3.6 to 3.2) and correlated with weight for age index, LBM SDS, and lung disease related conditions. Multiple regression analysis showed that only LBM remained independently related to IGF-I, suggesting that the relation of IGF-I to LBM was independent of weight and that the correlation between IGF-I and the respiratory conditions was related to the level of LBM. IGF-I SDS at the first evaluation was lower for the patients who lost > or =5% of weight for age index or > or =1 SD of LBM between the two evaluations. CONCLUSION: Low levels of IGF-I could be crucial for clinical outcome by impairing LBM and respiratory function. IGF-I could be a tool for nutritional evaluation by identifying the CF patients at risk of LBM depletion.

Prepubertal growth in children with long-term parenteral nutrition.

In children who depend on long-term parenteral nutrition (PN), a major goal is to obtain optimal growth. The aim of this retrospective study was to analyze growth in children on long-term cyclic nocturnal home PN, over at least 8 years before puberty. Nine boys and 7 girls were studied. Their mean age at the time of study was 11 years with a mean PN duration of 10.5 (8.6-16.4) years. Diseases were short bowel syndrome (5), intractable diarrhea (4), chronic intestinal pseudo-obstruction (4) and long segment Hirschsprung's disease (3). In each child, periods of at least 2 years were analyzed: either periods of regular growth (R: height gain >50th percentile), or slow growth (S: height gain < or =25th percentile). Results were expressed as mean +/- SD. Comparisons were performed using either Student's test for unpaired data or Wilcoxon's test for paired data. PN provided a mean of 224 +/- 80 mg nitrogen/kg/day and 43 +/- 14 kcal/kg/day equivalent to 50% of recommended supplies. At the time of study, the population presented with weight (W) = -0.7 +/- 0.8 SD and height (H) = -1.5 +/- 1.3 SD. The difference between W and expected W for H (W/H) was significant (p < 0.002). W/H ratio was 105 +/- 11%. For the total PN duration, weight gain was +0.2 +/- 1.5 SD and height loss was -0.75 +/- 1.4 SD. An excess weight gain occurred in parallel with the deflection of height gain. Of the 16 children, regular prepubertal growth was achieved in 4 only. The other 12 showed alternate periods of R and S. In 8 of them, 26.5 years of R and 33.5 years of S were compared, each child being his own control. PN nitrogen and energy supplies were significantly higher during R periods than during S periods. In the absence of any disease or treatment explaining the failure to thrive, inadequate PN supplies, especially in terms of nitrogen supply, are thought to be responsible for a negative nitrogen balance and slowed growth. In case of any deflection away from the individual growth curve, it is recommended to adjust the PN supply early, especially nitrogen supply.