belgian journal of paediatrics · belgian journal of paediatrics • 2016 - vol. 18 - nr.3 223...

BELGISCHE VERENIGING VOOR KINDERGENEESKUNDE SOCIÉTÉ BELGE DE PÉDIATRIE

2016 - Volume 18 - number 3 - September

VV.U./E.R. S. Cadranel (ULB), M. Raes (KUL)

Gasthuisberg, Herestraat 49, 3000 Leuven

E-mail: [email protected]

QUARTERLYISSN 2466-8907

Belgian Journalof Paediatrics

BJP

Articles Set-up of a paediatric home mechanical ventilation centre and review of the literature on this topic.

Round Table “Fat and Child’s brain”.

De rol van lipiden bij pediatrische neurometabole aandoeningen.

Les graisses dans la nutrition néonatale.

Discussion - Discussie.

Case Report Neonatale enterovirusinfectie.

Staphylococcus Aureus discitis in a child with Crohn’s Disease treated with Infliximab: A case report.

Acute respiratory distress during colonoscopy preparation: case report and brief overview of literature.

State of the Art Inborn errors of immunity: the natural or innate immune system and phagocyte defects.

Made In Belgium Down syndrome, an ENT perspective.

Endothelial dysfunction in obese children: shifting the balance between endothelial damage and repair?

Publication of the Belgian Society of Paediatrics

Belgische Vereniging voor KindergeneeskundeSociété Belge de Pédiatrie

mailto:[email protected]?subject=

Belgian Journal of Paediatrics • 2016 - Vol. 18 - Nr.3 219

FOUNDING EDITOR

L. Corbeel

REDACTEURS EN CHEF - EDITEURS RESPONSABLES HOOFDREDACTEURS - VERANTWOORDELIJK UITGEVERS

S. Cadranel M. Raes

CO-REDACTEURS

N. Francotte M. Wojciechowski

UNIVERSITÉS-UNIVERSITEITEN

G. Buyse (UZL) J. De Schepper (UZB) P. Lepage (ULB) V. Schmitz (ULG) J. Vande Walle (UZG) S. Verhulst (UZA)

SPECIALITES - SPECIALISMEN

Cardiologie M. Gewillig Endocrinologie J. De Schepper Gastroenterologie I. Hoffman Hemato-, Oncologie A. Uyttebroeck Immunologie I. Meyts Intensieve zorgen/Soins intensifs D. Biarent Neurologie L. De Meirleir Neonatologie B. Van Overmeire (C. Lecart) Nephrologie J. Vande Walle (E. Levtchenko) Pneumologie J. Hellinckx Reumatologie en Autoimmuunziekten/ Rhumatologie et maladies auto-immunes C. Wouters

VERENIGINGEN – GROUPEMENTS

V.V.K Ann De Guchtenaere G.B.P.F P. Bauche

BUREAU DE LA SOCIETE BELGE DE PEDIATRIE BUREAU VAN DE BELGISCHE VERENIGING VOOR KINDERGENEESKUNDE

VOORZITTER A. MALFROOT PRÉSIDENT VICE-VOORZITTER C. VAN GEET VICE-PRESIDENT SCHATBEWAARDER D. DE WOLF TRÉSORIER SECRETARIS C. VERMYLEN / M. RAES SECRÉTAIRE PAST-PRESIDENT P. LEPAGE PAST-PRESIDENT PARTNERSHIP S. CADRANEL PARTNERSHIP

Redactieraad / Comité de rédaction


• Editorial 223 S. Cadranel - M. Raes

• Articles Set-up of a paediatric home mechanical ventilation centre and review of the literature on this topic. 227 Lieve Boel

Round Table “Fat and Child’s brain”. 239 Introduction

De rol van lipiden bij pediatrische neurometabole aandoeningen. 240 Luc Régal

Les graisses dans la nutrition néonatale. 244 Thibault Senterre

Discussion - Discussie. 247

• Cases Reports Neonatale enterovirusinfectie. 253 Annelies Deelen

Staphylococcus Aureus discitis in a child with Crohn’s Disease treated with Infliximab: A case report. 257 Klaar Vergaelen

Acute respiratory distress during colonoscopy preparation: case report and brief overview of literature. 263

Jean Toelen

• State of the Art

Inborn errors of immunity: the natural or innate immune system and phagocyte defects. 267 Isabelle Meyts

• Made in Belgium

Down syndrome, an ENT perspective. 273 Mieke Maris

Endothelial dysfunction in obese children: shifting the balance between endothelial damage and repair? 277 Luc Bruyndonckx

• New publication guidelines. 282

Contents


Dankzij de steun van onze partners kan de BVK over verschillende domeinen van de Volksgezondheid communiceren.

C'est grâce au soutien de nos partenaires que la SBP parvient à communiquer dans les divers domaines de la Santé Publique en Pédiatrie.

Partners van BVK / Les partenaires de la SBP


After this unusually bright and sunny summer we resume our task of publishing scientific articles in our BJP with the clear goal to run for international recognition. Obviously it will not be an easy task but we are confident that we can reach this objective in a not too far away future. Our team is composed by the two chief editors (French and Dutch speaking to represent our multilingual country) but also the supporting editors Nadine Francotte from CHC - Liège and Marek Wojciechowski from UZA – Antwerp and our dynamic and effective secretary, Natacha Meignen. Our structure comprises also representatives of the 7 Belgian universities, of the regional societies (VVK and GBPF) and of the different paediatric sub-specialties. The board meets at least 4 times per year and we need to restructure our organization to be able to gather all the representatives at least once a year in a general assembly to collect their ideas (and/or critics) and discuss over the future developments of our review.

Some history to remind that Acta Paediatrica Belgica, the former official journal of the Belgian Society of Paediatrics, merged with its Swiss and Hungarian counterparts in what is now the European Journal of Paediatrics referred in Medline. However, despite Lucien Corbeel and Willem Proesmans efforts the EJP harboured rare contributions of young Belgian authors. For that reason, Prof. Corbeel founded the Mini-Acta followed by the bilingual Journal du Pédiatre Belge – Tijfdschrift van de Belgische Kinderarts directed, since 2007, by a new editorial board with Paul Casaer and Samy Cadranel as chief-editors.

Besides the usual articles and case reports and also the thematic articles we inaugurated several new sections such as “made in Belgium” in order to publish the summaries of paediatric PhD Belgian theses, the “surgeon’s corner”, naturally devoted to the promotion of the dialogue between paediatricians and paediatric surgeons and recently a “state of the art” by invited experts in fields that should benefit to the understanding and knowledge of our readers. We have also published one to two-year public health campaigns for the promotion of breastfeeding and the defence of prevention and vaccination. A future campaign on metabolic and orphan diseases is in preparation.

In this September issue you will find an original article on home mechanical ventilation, several interesting case reports, made in Belgium contributions and a comprehensive and practical state of the art by Isabelle Meyts on immunodeficiences for the paediatrician.

Last but not least, the report of the round table organized last May by the Belgian Society of Paediatrics on the role of lipids on the neonatal brain and on neurological disorders presented by two experts, Drs Luc Regal in Dutch and Thibault Senterre in French. The following discussion moderated by Professor Philippe Goyens was animated by questions and comments by the invited participants selected for their interest in the field. We believe that this round table should be followed by others. For the first time our editorial is not written in French and Dutch but in the current modern language not only for business but also for scientific communications, a kind of modern Latin that every scientist should be able to understand. Your comments and feedback are solicited and we will pay attention to your critics and suggestions in order to improve the quality of our BJP, an official tribune of Belgian Society of Paediarics.

Samy Cadranel and Marc Raes, chief editors.

Uw vragen of commentaarVos questions ou commentaires

Comité de rédaction - Redactieraad M. Raes - S. Cadranel

Gasthuisberg - Kindergeneeskunde

Herestraat 49 - 3000 Leuven E-mail [email protected]


Editorial

mailto:[email protected]

“Grenzen in pediatrie““Frontières en pédiatrie”

Voorzitter - Président : Mark Wojciechowski / UZ AntwerpenOrganisatiecomité - Comité d’organisation :Berten CeulemansMargo HagendorensLudo Mahieu

Iris MallinusMarjolein MattheijNicolette Moes

Els Van de VijverDavid Van LaereAalt Van Roest

Renée Van ZitterenStijn VerhulstErika Vlieghe

Event Coordinator : Anne-France De Meyer:Tel 02/375 36 26 • [email protected] Avenue Carsoel, 102 B-1180 Bruxelles

Antwerpen Hilton Hotel23-24 Maart - Mars 2017

BVK/SBP Congres 2017

45steème

Jaarlijks Congres van de Belgische Vereniging

voor Kindergeneeskunde

Congrès Annuel de la Société Belge de PédiatrieBELGISCHE VERENIGINGVOOR KINDERGENEESKUNDESOCIÉTÉ BELGE DE PÉDIATRIE

Kuns

tena

ar -

Art

iste:

: Ka

atje

Ver

mei

ren


Renée Van ZitterenStijn VerhulstErika Vlieghe

Dear colleagues,

The yearly congress of the Belgian Society of Paediatrics in 2017 will be held in Antwerp on march 23th and 24th. The general theme is frontiers in paediatrics. Frontiers include borders, limits and interfaces. Migration, multicultural medicine, emerging diseases, NGO’s all relate to borders. Extreme prematurity, end of life, behavioural problems, new diagnostic, therapeutic or technological possibilities relate to limits. Interfaces between subspecialties could be discussed in interdisciplinary sessions. We hope that the congress can push boundaries, broaden our horizons, let us reflect on social and ethical issues and increase our medical knowledge. On behalf of the Belgian Society of Paediatrics and our scientific committee I invite you to save these dates and I hope to welcome you at the congress.

Beste collega’s

In 2017 zal het jaarlijks congres van de Belgische Vereniging voor Kindergeneeskunde doorgaan op 23 en 24 maart in Antwerpen. Het algemeen thema is grenzen in de kindergeneeskunde. Grenzen in de betekenis van landsgrenzen, limieten of raakvlakken. Landsgrenzen verwijst onder meer naar migratie, multiculturele geneeskunde, oprukkende ziekten, NGO’s. Limieten onder andere naar extreme prematuriteit, levenseinde, gedragsproblemen, nieuwe diagnostische, therapeutische of technologische mogelijkheden. Raakvlakken tussen subspecialiteiten kunnen verkend worden tijdens de interdisciplinaire sessies. Wij hopen dat het congres grenzen kan verleggen, onze horizon verruimen, ons laat nadenken over maatschappelijke en ethische problemen en onze medische kennis uitbreiden. Namens de Belgische Vereniging voor Kindergeneeskunde en ons wetenschappelijk comité nodig ik u uit om de datum al vast te leggen en hoop ik u op het congres te mogen verwelkomen.

Chers collègues,

En 2017 le congrès annuel de la Société Belge de Pédiatrie se tiendra à Anvers, les 23 et 24 mars. Le thème général est frontières en pédiatrie, frontières géographiques, limites ou interfaces. La migration, la médecine multiculturelle, les maladies émergentes, les ONG ont tous un rapport aves les frontières géographiques. Limites peut avoir un rapport avec entre-autre la prématurité extrême, la fin de la vie, les problèmes du comportement, de nouvelles possibilités diagnostiques, thérapeutiques ou technologiques. Les interfaces entre les surspécialités peuvent être explorées dans les sessions interdisciplinaires.Nous espérons que le congrès puisse déplacer nos frontières, élargir notre horizon, nous permet de réfléchir à des problèmes sociétaux et éthiques et augmente nos connaissances médicales. Au nom de la Société belge de Pédiatrie et de notre comté scientifique je vous invite à réserver les dates et j’espère pouvoir vous accueillir nombreux au congrès.

Mark WojciechowskiVoorzitter - Président / UZ Antwerpen


Set-up of a paediatric home mechanical ventilation centre and review of the literature on this topic.

L. Boel ¹, F. De Baets ².

¹ Paediatrics, Ghent University Hospital.

² Paediatric Pulmonology, Ghent University Hospital.

[email protected]

Article

AbstractAim: The number of children on mechanical ventilation at home is increasing. In 2004 a paediatric home mechanical ventilation (HMV) centre was started at Ghent University Hospital, Belgium. We would like to report and compare our data with those reported in the literature.Methods: A retrospective chart review was performed of all children who were started on home mechanical ventilation between 2004 and September 2014 at the Ghent University Hospital, Belgium. A literature search was performed in PubMed. Results: Between 2004 and September 2014, 18 children were started on home mechanical ventilation in our centre. The majority of the patients suffer from neuromuscular diseases, is ventilated non-invasively and uses the ventilator only during sleep. Conclusion: Children on home mechanical ventilation are an increasing population, which is also the case in our paediatric home mechanical ventilation centre.

KeywordsHome mechanical ventilation, children

Abbreviations: BPD bronchopulmonary dysplasiaCCHS congenital central hypoventilation syndromeCLD chronic lung diseaseCO

2 carbon dioxide

CPAP continuous positive airway pressureFVC forced vital capacityHMV home mechanical ventilationNIV non-invasive ventilationOSAS obstructive sleep apnoea syndromePaCO

2 partial pressure of carbon dioxide in arterial blood

PaO2 partial pressure of oxygen in arterial blood

PPV positive pressure ventilationSMA spinal muscular atrophySMARD spinal muscular atrophy with respiratory distress

Over time, mechanical ventilation has been the subject of a strong (r)evolution as a result of the increasing technological and medical knowledge in this field. At first, respiratory support was used only in intensive care units. Later, home mechanical ventilation (HMV) became a possibility, first for adults, and subsequently for children. HMV can be provided invasively, through a tracheostomy, or non-invasively using a mask. Due to the increasing use of non-invasive ventilation (NIV), the number of children on home respiratory support is increasing. The reported prevalence varies between 0,7/100.000 children in 1993 in Japan and 3,4/100.000 children in 2000 in Switzerland ¹.

HMV can be started for different reasons, including chronic hypoventilation accompanied with hypoxemia and hypercapnia, airway obstruction or failure to wean. A broad spectrum of diseases can be the cause of respiratory failure, which can be classified into four different groups as neuromuscular, airway and/or respiratory, central nervous system and other disorders. In 2004 the first child was initiated on HMV at Ghent University Hospital, Belgium. Here, we report on the first ten years of our paediatric HMV centre and compare our data with those reported by other centres, as described in the literature.

Introduction



Patients and MethodsA retrospective chart review was performed of all children who were started on home mechanical ventilation between 2004 and September 2014 at the Ghent University Hospital, Belgium. Home mechanical ventilation is defined as invasive or non-invasive respiratory support, either by the use of positive pressure ventilation (PPV) or continuous positive airway pressure (CPAP). Data obtained for each patient include sex, year of birth, diagnosis, reason for initiating HMV, age at which HMV was started and, if possible, stopped, method of respiratory support, time per day the ventilator is used, as well as positive effects and complications.Approval for this study was obtained from the Ethics Committee of Ghent University Hospital.A literature search was performed in PubMed using ‘home ventilation’ and ‘children’ as search terms. Articles were selected if they were published between 2008 and 2013, written in English, French or Dutch and report about mechanical ventilation in children at home.

ResultsBetween 2004 and September 2014, 18 children, ten boys and eight girls, were started on HMV. The patient characteristics are shown in table 1. The majority of the patients (11/18) suffer from a neuromuscular disease. These include two patients with merosine deficiency and four with spinal muscular atrophy (SMA) as well as one patient each with alphadystorglycanopathy, SMARD, congenital Steinert disease, congenital myasthenia or myopathy of unknown origin. Three of the treated children have an airway problem being either obstructive sleep apnoea syndrome (OSAS), Down syndrome with OSAS or Goldenhar syndrome. One child has chronic lung disease and paralysis of the phrenic nerve because of birth injury. Two patients have congenital central hypoventilation syndrome (CCHS). One child suffers from achondroplasia with medullopathy and could not be weaned from ventilation postoperatively.

In four children HMV was started because of failure to wean from invasive ventilation while the other patients were initiated on an elective basis. The latter were characterized as having progressive respiratory insufficiency. This became clinically apparent as the occurrence of recurrent respiratory infections (6/18) and/or atelectasis (3/18), anorexia (3/18), disturbed sleep with nocturnal sweating (4/18), morning headaches (1/18) and daytime sleepiness (2/18). Accordingly a sleep study in these patients showed oxygen saturation levels under 90% for a large part of the night (more than two hours) as well as increased values for transcutaneously measured CO

2, confirming respiratory insufficiency and the

need to start HMV. On HMV, the results of a follow-up sleep study normalized or clearly improved. Furthermore, children and their parents mentioned an increased quality of life: less respiratory infections and hospitalisations, better appetite, less daytime sleepiness and better school performances.The majority of the children (14/18) are ventilated non-invasively and use a nasal mask or nose-mouth mask. Of these children nine suffer from a neuromuscular disease, two patients each have CCHS or OSAS and one child suffers from Goldenhar syndrome. Fifteen patients use the ventilator only while sleeping, but in the event of a respiratory infection HMV is continued during the day. Two of the three children with 24-hour ventilator dependency have a tracheostomy.The most frequent reported complications are mask-related and in young children. Pressure sores were reported in four patients (three with a neuromuscular disease, one with CCHS) and midface hypoplasia in one child with CCHS. These problems were solved by switching to another type of mask or by using different masks alternately.In the time frame studied (2004-2014), one child with chronic lung disease and paralysis of the phrenic nerve could be weaned from the ventilator after seven months. Unfortunately one child died after two years on HMV because of progression of his underlying neuromuscular disease. The time of follow-up on HMV has a broad range (range 1-120 months; median 16,5 months; mean 35,7 months), because the number of children started on HMV varies by year and is increasing. The number of children started on HMV per year is shown in figure 1.

Article

Table 1: Description of the 18 children started on HMV.

Disease Sex Type of HMV Age at start Use/dayNeuromuscularMerosine deficiency F mask, PPV 8 years sleep

Merosine deficiency M mask, PPV 14 years sleep

Alphadystoglycanopathy M tracheostomy, PPV 14 months 24 hours

SMA 1 F mask, PPV 2 years sleep



SMA 2 M mask, PPV 3 years sleep

SMARD 1 M tracheostomy, PPV 13 months sleep

Congenital Steinert disease F mask, PPV 15 months sleep

Congenital myastenia F mask, CPAP 13 years sleep

Myopathy eci M mask, PPV 11 years 24 hours

Airway obstructionOSAS M mask, CPAP 16 months sleep

Down syndrome + OSAS M mask, CPAP 11 years sleep

Goldenhar syndrome F mask, CPAP 12 years sleep

Chronic lung diseaseCLD + paralysis phrenic nerve M tracheostomy, CPAP 5 months 24 hours

Central nervous systemCCHS F mask, PPV neonatal sleep

CCHS M mask, PPV neonatal sleep

OtherAchondroplasia M tracheostomy, PPV 22 months sleep

CCHS = congenital central hypoventilation syndrome; CLD = chronic lung disease; CPAP = continuous positive airway pressure; F = female; M = male; PPV = positive pressure ventilation; SMA = spinal muscular atrophy; SMARD = spinal muscular atrophy with respiratory distress


Article

Figure 1: Number of children started on HMV per year. DiscussionA total of 3479 paediatric patients on HMV have been described in 17 articles 1-17, summarized in table 2. As obvious from the literature, children on HMV suffer from different underlying diseases. Some disorders can be classified in different ways, but in general they are split up into four groups. Children with a neuromuscular disease are the largest group (1699/3479; 48,89%), followed by respiratory and airway disorders as a second group (1054/3479; 30,2%), central nervous disorders as a third category (538/3479; 15,5%) and finally other, not otherwise classified, diseases (188/3479; 5,4%). Besides these four major categories there are children with a multisystem disorder or in whom more factors contribute to the respiratory insufficiency. Although the number of children on HMV at Ghent University Hospital, Belgium is small, these four groups of underlying pathologies can be recognised, with the majority of patients being children with neuromuscular disorders as well (11/18).

Table 2: Underlying diseases of 3479 patients described in 17 articles. (Part 1)

Article Underlying disorder Number of patientsRacca, Berta et al. ¹ Neuromuscular disorders 178/362

Lung and upper respiratory diseases 64/362

Hypoxic (ischemic) encephalopathy 48/362

Abnormal ventilation control 44/362

Spinal cord injury 11/362

Chest anomalies 16/362

Other 1/362

Peckan et al. ² Neuromuscular disease 16/27

Respiratory disease 6/27

Congenital heart disease 3/27

Storage disease 2/27

Paulides et al. ³ Neuromuscular disorders 130/197

Central nervous system disorders 33/197

Chronic pulmonary or airway diseases 13/197

Congenital scoliosis 21/197

Sovtic et al. 4 Neuromuscular 18/29

Cystic fibrosis 4/29

OSAS 5/29

Kyphoscoliosis, CCHS 2/29

Chatwin et al. 5 Scoliosis 8/28

SMA type 2 4/28

Poliomyelitis 3/28

Diaphragm paralysis 4/28

DMD 4/28

Myotonic dystrophy 1/28

Multiple sclerosis 1/28

Motor neuron disease 1/28

Thoracoplasty 1/28

Restrictive lung disease 1/28

Racca, Bonati et al. 6 Neuromuscular 187/378

Cerebral palsy 52/378

Upper airway disorders, OSAS 45/378

CCHS 44/378

Spinal cord injury 13/378

Chest wall deformity 16/378

Chronic lung diseases 20/378

Neurofibromatosis 1/378


Article

Article Underlying disorder Number of patientsTibballs et al. 7 OSAS 55/168

Neuromuscular conditions 42/168

Tracheo-bronchomalacia 23/168

CP-kyphoscoliosis 20/168

Acquired and congenital central hypoventilation 15/168

Chronic lung disease, pulmonary hypoplasia 8/168

Quadriplegia: traumatic, tumour, infective 5/168

Wallis et al. 8 Central nervous system 168/933

Musculoskeletal 402/933

Respiratory 343/933

Unclassified 20/933

Goodwin et al. 9 Neuromuscular 34/106

Airway 37/106

Central 33/106

Parenchymal lung disease 2/106

Hsia et al. 10 Neurologic/neuromuscular disease 100/139

Airway/lung dysfunction 19/139

Metabolic/Genetic abnormalities 16/139

Congenital heart disease, postoperative diaphragmatic paresis

4/139

Edwards, Kun, Keens 11 Chronic pulmonary disease 120/228

Ventilatory muscle weakness 62/228

Central hypoventilation syndromes 46/228

Com et al. 12 Neuromotor dysfunction 47/91

Chronic lung disease 26/91

(Multiple) congenital anomalies, skeletal disorders 18/91

Amin et al. 13 Central nervous system 109/379

Musculoskeletal 132/379

Respiratory 124/379

Other 14/379

Divo et al. 14 Neuromuscular disease 152/221

Obstructive lung disease 51/221

Other: chest wall or thoracic 18/221

Meltzer et al. 15 Neuromuscular/nervous system 11/30

Chronic lung disease 8/30

Congenital anomaly 11/30

Reiter et al. 16 Neuromuscular 26/54

Respiratory 14/54

Syndromic 14/54

Kun et al. 17 Chronic pulmonary disease 66/109

Ventilatory muscle weakness 23/109

Central hypoventilation syndrome 20/109

CCHS = congenital central hypoventilation syndrome; CP = cerebral palsy; DMD = Duchenne muscular dystrophy; OSAS = obstructive sleep apnoea syndrome; SMA = spinal muscular atrophy

Table 2: Underlying diseases of 3479 patients described in 17 articles. (Part 2)

HMV can be provided invasively, by tracheostomy, bypassing the upper respiratory tract, or non-invasively. Non-invasive ventilation is delivered through an external interface between the ventilator and the patient. A nasal mask is most frequently used, but a mouth-nose mask, facemask or mouthpieces are other possibilities. The choice of the mask depends on the age, facial characteristics, amount of secretions, risk of aspiration, cooperation, patient’s preference and severity of respiratory problems of the patient. Complications with a certain type of mask require a change to another type. Whatever type of mask is used it should be light, soft, transparent, well fitting but not hermetically closed, with a limited air leak, low resistance to the airflow and a limited area of dead space 18, 19.The use of invasive versus non-invasive ventilation seems to depend on local

practice. Reported indications for the use of invasive ventilation are airway malacia, young age, failure to wean, profuse airway secretions, swallowing problems, limited cooperation, cerebral palsy, neuromuscular disorders, progression of the underlying disease and ventilation expected to be necessary during a long period or more than 12 hours a day 1, 6-9, 13, 16. Some authors consider invasive ventilation, by a tracheostomy, as the first choice in the paediatric population 3, 14. However, the disadvantages of a tracheostomy have to be taken in account when this choice is made, especially since nowadays non-invasive ventilation is an alternative in most cases, except in some patients with 24-hour ventilator dependency.Other studies report that children with musculoskeletal, neuromuscular and airway or respiratory disorders mainly use non-invasive ventilation 7, 8.


Article

Furthermore, the use of non-invasive ventilation seems to increase with advancing age 1, 6. This is attributed by the natural course of neuromuscular diseases in which respiratory insufficiency increases with age. In the retrospective chart review of Goodwin et al. 9 there is a trend to start with non-invasive ventilation more frequently. Elsewhere, OSAS refractory to adenotonsillectomy and disorders of the upper airways are reported indications for the use of non-invasive ventilation 6, 19. In our centre we preferentially use non-invasive ventilation, even in young children as well as in patients who will be dependent on home mechanical ventilation for an extended duration, even in case of lifelong necessity of HMV as in the children with CCHS.

Invasive and non-invasive ventilation both generate a therapeutic airway pressure by either CPAP or PPV. The mode used depends on the underlying pathology. In patients with obstruction of the airway, as in OSAS, CPAP should be used. On the other hand, in patients with hypoventilation or a problem in the central regulation of breathing, as in neuromuscular diseases and CCHS respectively, PPV should be used.

HMV can be used continuously, intermittent (during respiratory exacerbations only) or during sleep. In the article by Wallis et al. 8 the majority of children (658/933; 70,5%) are ventilated only while sleeping, whereas 88 out of 933 children (9,4%) are ventilated 24 hours a day. The remainder of the patients use HMV intermittently.Similarly in our population the majority of children (15/18) is ventilated only while sleeping. In the event of a respiratory exacerbation they use their ventilator during the day as well. Only three children are ventilated continuously.

When to start HMV is a difficult question to answer. Guidelines concerning this topic are scarce and rather vague. Consequently, when HMV is started or when a sleep study is performed depends on local practices. Respiratory insufficiency is most often preceded by nocturnal hypoventilation demonstrated by frequent arousal, daytime sleepiness and cognitive changes. If a sleep study is performed during this period nocturnal hypoventilation can be proven and subsequently HMV can be initiated 20. However, signs of nocturnal hypoventilation only occur when the nocturnal hypoventilation is significant. Therefore in children with neuromuscular diseases routine evaluation of the respiratory function should be performed to prevent and manage complications 21, 22. For children with Duchenne muscular dystrophy guidelines concerning respiratory follow-up exist 21, 22 which could be used for all children with progressive neuromuscular disorders. The guideline by Bushly et al. 22 proposes to perform spirometry at least once a year in all ambulatory children with Duchenne muscular dystrophy from the age of six on. In non-ambulatory patients every six months pulse oximetry, spirometry and peak cough flow should be performed and if possible, maximum inspiratory and expiratory pressures should be measured. If non-ambulatory patients are suspected of hypoventilation, have a forced vital capacity (FVC) under 50% predicted or are using assisted ventilation, awake end-tidal CO

2 level should

be measured by capnography every year. A sleep study should be performed in patients with baseline FVC under 40% predicted, awake baseline blood or end-tidal CO

2 higher than 45 mmHg, awake baseline oxygen saturation under 95%,

FVC less than 1,25 liters in teenage or older patients and if signs or symptoms of hypoventilation exist. According to Chatwin et al. 23 nocturnal NIV has to be started, without nocturnal monitoring of transcutaneous CO

2 and oximetry, in

patients with chronic awake arterial CO2 higher than 6,5 kPa (~ 48,75 mmHg)

and in patients with nocturnal transcutaneous CO2 above 6,5 kPa for more than

50% of the night.

However, we would like to point out that an ethical consideration should be made before starting HMV. One should ask the questions whether starting HMV will increase quality of life or whether it will only prolong life? Since most children with respiratory failure are vulnerable patients with persistent risk of acute infections,

frequent hospitalisation, progression of their underlying disease and a high risk of decease, the answers to these questions should be taken into respect.On another level, we cannot lose sight of the parents of these patients, because in the care for their ventilator dependent child they have multiple tasks to accomplish and a heavy burden to carry while often feeling like “being the lifeline”. This applies to all parents of children with HMV, but if their child needs respiratory support 24-hours a day and/or the child has a tracheostomy the burden is even higher. Because of the important and often vital role they take on, parents become experts in the care for their child and a new “normal” daily life arises 15, 24-26.

Positive effects described after starting HMV include significant improvement in PaCO

2- and PaO

2-values, weight gain, longer survival in particular groups

of patients, less frequent occurrence of respiratory decompensation and non-elective hospitalisation as well as better quality of life. Furthermore HMV has a higher cost-efficiency than hospitalisation 4, 7, 24, 27.Once started, HMV does not necessarily have to be used lifelong. It can be used as a “bridge to transplant” as in cystic fibrosis patients or it can be stopped if the underlying condition ameliorates as in laryngomalacia, tracheobronchomalacia, BPD, OSAS, micrognathia and Prader-Willi syndrome 2-4, 9, 28. We had one child with CLD and phrenic nerve palsy who successfully discontinued the use of HMV after seven months. Besides positive effects, HMV can have negative effects as well. In non-invasive ventilation masks are used which can cause skin lesions or midface hypoplasia. This was reported in five of our patients. In case of low airflow there is a risk of rebreathing whereas a risk of inhalation of secretions exists if the child cannot remove the mask independently 2, 4, 18, 19. Life-threatening complications are reported and this more frequent in younger patients. Reiter et al. 16 report the occurrence of at least one emergency situation per 4, 6 patient years. Most of these complications can be managed at home without sequelae, but the outcome depends on the immediate detection, competence and availability of the parents or caregivers 3, 7, 12, 13, 16, 28, 29. Paulides et al. ³ report a mortality rate of 22%. The majority of the deaths are related to the underlying disorder and in most cases, patients’ lives were probably prolonged by the use of HMV for several years. One of our patients, a boy with alphadystoglycanopathy, died at the age of three because of progression of his neuromuscular disorder, after two years on HMV.

Although HMV in children is a relatively recent practice in our hospital, we clearly see an increase in the number of patients started on this therapy over time. In the first years a maximum of two children were started per year, while in the last years, 2013 and 2014, four and six children were started on HMV respectively, corresponding to a two to threefold increase. An increase over time is also reported in other countries. In the USA a fourfold increase between 1987 and 2006 was described 12, while reports from Canada showed a doubling of invasively ventilated children and a fivefold increase of non-invasive ventilation over 20 years 13. In Europe on the other hand, in Italy a sevenfold increase was reported between 1992 and 2010 27, while in the UK a ninefold increase was observed between 1998 and 2008 8. The most spectacular growth, a fifteen fold increase over 30 years, was seen in the Netherlands ³.

ConclusionHMV increases the quality of life in children with neuromuscular diseases, it can support a transient period of respiratory insufficiency or sustain respiration while waiting for a lung transplantation. Children on HMV are a growing patient population in which four groups of underlying pathology can be distinguished. The use of HMV has been proven to be safe and efficient. In our hospital the use of HMV in children was initiated in 2004. Over ten years there was a clear increase in the number of HMV treated patients. Patient characteristics, complications and subjective positive effects are comparable to those reported in the literature.


1. Racca F, Berta G, Sequi M, et al. Long-term home ventilation of children in Italy: A national survey. Pediatr Pulmonol. 2011; 46: 566-572.

2. Pekcan S, Aslan AT, Kiper N, et al. Home mechanical ventilation: outcomes according to remoteness from health center and different family education levels. Turk J Pediatr. 2010; 52: 267-273.

3. Paulides FM, Plötz FB, Verweij-van den Oudenrijn LP, van Gestel JPJ, Kampelmacher MJ. Thirty years of home mechanical ventilation in children: escalating need for pediatric intensive care beds. Intensive Care Med. 2012; 38: 847-852.

4. Sovtic A, Minic P, Vukcevic M, Markovic-Sovtic G, Rodic M, Gajic M. Home mechanical ventilation in children is feasible in developing countries. Pediatr Int. 2012; 54: 676-681.

5. Chatwin M, Nickol AH, Morrell MJ, Polkey MI, Simonds AK. Randomised trial of inpatient versus outpatient initiation of home mechanical ventilation in patients with nocturnal hypoventilation. Respir Med. 2008; 102: 1528-1535.

6. Racca F, Bonati M, Del Sorbo L, et al. Invasive and non-invasive long-term mechanical ventilation in Italian children. Minerva Anestesiol. 2011; 77(9): 892-901.

7. Tibballs J, Henning R, Robertson CF, et al. A home respiratory support programme for children by parents and layperson carers. J Paediatr Child Health. 2010; 46: 57-62.

8. Wallis C, Paton JY, Beaton S, Jardine E. Children on long-term ventilatory support: 10 years of progress. Arch Dis Child. 2011; 96 (11): 998-1002.

9. Goodwin S, Smith H, Hewer SL, et al. Increasing prevalence of domiciliary ventilation: changes in service demand and provision in the South West of the UK. Eur J Pediatr. 2011; 170: 1187-1192.

10. Hsia SH, Lin JJ, Huang IA, Wu CT. Outcome of long-term mechanical ventilation support in children. Pediatr Neonatol. 2012; 53: 304-308.

11. Edwards JE, Kun SS, Keens TG. Outcomes and causes of death in children on home mechanical ventilation via tracheostomy: An institutional and literature review. J Pediatr. 2010; 157(6): 955-959.

12. Com G, Kuo DZ, Bauer ML, et al. Outcomes of children treated with tracheostomy and positive-pressure ventilation at home. Clin Pediatr. 2013; 52(1): 54-61.

13. Amin R, Sayal P, Syed F, Chaves A, Moraes TJ, MacLusky I. Pediatric long-term home mechanical ventilation: Twenty years of follow-up from one Canadian center. Pediatr Pulmonol. 2014; 49 (8): 816-824; Epub 2013 Sep 2.

14. Divo MJ, Murray S, Cortopassi F, Celli BR. Prolonged mechanical ventilation in Massachusetts: The 2006 prevalence survey. Respir Care. 2010; 55(12): 1693-1698.

REFERENCES:

15. Meltzer LJ, Boroughs DS, Downes JJ. The relationship between home nursing coverage, sleep and daytime functioning in parents of ventilator-assisted children. J Pediatr Nurs. 2010; 25(4): 250-257.

16. Reiter K, Pernath N, Pagel P, et al. Risk factors for morbidity and mortality in pediatric home mechanical ventilation. Clin Pediatr. 2011; 50(30): 237-243.

17. Kun SS, Edwards JD, Davidson Ward SL, Keens TG. Hospital readmissions for newly discharged pediatric home mechanical ventilation patients. Pediatr Pulmonol. 2012; 47: 409-414.

18. Pavone M, Verrillo E, Caldarelli V, Ullmann N, Cutrera R. Non-invasive positive pressure ventilation in children. Early Hum Dev. 2013; 89: S25-S31.

19. Brown KA, Bertolizio G, Leone M, Dain SL. Home noninvasive ventilation What does the anesthesiologist need to know? Anesthesiology. 2012; 117(3): 657-668.

20. Fauroux B, Lofaso F. Non-invasive mechanical ventilation: when to start for what benefit? Thorax. 2005; 60: 979-980.

21. Finder JD, Birnkrant D, Carl J, et al. Respiratory care of the patient with Duchenne muscular dystrophy: an official ATS consensus statement. Am J Respir Crit Care Med. 2004; 170: 456-465.

22. Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol. 2010; 9: 177-189.

23. Chatwin M, Tan HL, Bush A, Rosenthal M, Simonds AK. Long term non-invasive ventilation in children: impact on survival and transition to adult care. PLoS One. 2015; 10(5).

24. Mah JK, Thannhauser JE, McNeil DA, Dewey D. Being the lifeline: The parent experience of caring for a child with neuromuscular disease on home mechanical ventilation. Neuromuscul Disord. 2008; 18: 983-988.

25. Boroughs DS, Dougherty J. A multidisciplinary approach to the care of the ventilator-dependent child at home. Home Healthc Nurse. 2010; 28(1): 24-28.

26. Toly VB, Musil CM, Carl JC. Families with children who are technology dependent: Normalization and family functioning. West J Nurs Res. 2012; 34(1): 52-71.

27. Gregoretti C, Ottonello G, Testa MBC, et al. Survival of patients with spinal muscular atrophy type 1. Pediatrics. 2013; 131(5): e1509-e1514.

28. Cristea AI, Carroll AE, Davis SD, Swigonski NL, Ackerman VL. Outcomes of children with severe bronchopulmonary dysplasia who were ventilator dependent at home. Pediatrics. 2013; 132(3): e727-e734.

29. Edwards JD, Kun SS, Keens TG, Khemani RG, Moromisato DY. Children with corrected of palliated congenital heart disease on home mechanical ventilation. Pediatr Pulmonol. 2010; 45: 645-649.

Article

Un prix de € 20.000 sera décerné par la SBP/BVK durant le

prochain congrès annuel de la SBP en Mars 2017. Il couronnera

l’auteur d’un Projet de recherche dans le domaine de la Pédiatrie.

Le Projet doit être planifié en relation avec une Université belge et

participer au développement de la Pédiatrie en Belgique.

Le règlement de ce prix est disponible sur le site

de la Société Belge de Pédiatrie (www.bvksbp.be).

Les mémoires doivent être adressés par voie électronique à

Mme Anne-France De Meyer

([email protected]),

secrétaire scientifique de la SBP/BVK avant le 30 Novembre 2016.

Un curriculum vitae doit être joint à la candidature.

Prix Bi-annuelpour le Soutien à un

Projet de Recherche de la SBP/BVK:

http://www.bvksbp.be/


Un prix de € 20.000 sera décerné par la SBP/BVK durant le

prochain congrès annuel de la SBP en Mars 2017. Il couronnera

l’auteur d’un Projet de recherche dans le domaine de la Pédiatrie.

Le Projet doit être planifié en relation avec une Université belge et

participer au développement de la Pédiatrie en Belgique.

Le règlement de ce prix est disponible sur le site

de la Société Belge de Pédiatrie (www.bvksbp.be).

Les mémoires doivent être adressés par voie électronique à

Mme Anne-France De Meyer

([email protected]),

secrétaire scientifique de la SBP/BVK avant le 30 Novembre 2016.

Un curriculum vitae doit être joint à la candidature.



1. Un prix de € 20.000 sera décerné par la SBP durant le prochain congrès annuel de la SBP en mars 2017. Il couronnera l’auteur d’un Projet de recherche dans le domaine de la pédiatrie. Le Projet doit être planifié en relation avec une Université belge et participer au développement de la pédiatrie en Belgique.

2. Les candidats doivent être pédiatres ou assistants en pédiatrie, membres de la SBP/BVK et diplômés médecins depuis moins de 10 ans au moment du dépôt de la candidature.

3. Une commission scientifique constituée à parts égales de membres du Bureau de la SBP/BVK et d’experts de Sociétés Européennes de Pédiatrie est chargée de rendre un avis. Cet avis est rendu dans le mois qui suit la réception des demandes. Il concerne tant l'intérêt scientifique des projets soumis que leur faisabilité et la pertinence des coûts.

4. Les guidelines seront disponibles sur le site de la SBP/BVK (www.bvksbp.be) dès le début du mois d’Octobre.

5. Les demandes complétées de manière électronique doivent être adressés à Mme Anne-France De Meyer ([email protected]), secrétaire scientifique de la SBP/BVK pour le 30 Novembre 2016 au plus tard. Les documents doivent être rédigés en langue anglaise. Un curriculum vitae doit être joint à la candidature.

6. Le Projet peut être cumulé à une ou plusieurs autres sources de financement.

7. Le Projet peut être soumis à 2 reprises à la commission scientifique.

8. Il est loisible à la SBP/BVK de décider, eu égard à la carence de candidatures, ou à l’insuffisance scientifique des travaux présentés, de ne pas attribuer le prix.

9. Les travaux seront présentés pendant le congrès lors de la session « Jeunes chercheurs ».

10. Le gagnant du Grant sera désigné pendant le congrès. Il est impératif que les lauréats soient présents lors de la proclamation des résultats pour la remise du Grant.



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Een prijs ter waarde van € 20.000 zal toegekend worden tijdens

het jaarlijkse congres van de BVK in Maart 2017 aan

de auteur van een onderzoeksproject op het vlak van

kindergeneeskunde. Het project moet gepland worden

in samenspraak met een Belgische universiteit en bijdragen tot de

ontwikkeling van de kindergeneeskunde in België.

Het reglement is beschikbaar op de site van de

Belgische Vereniging voor Kindergeneeskunde (www. bvksbp.be).

De scripties moeten elektronisch gestuurd worden naar Mevrouw

Anne-France De Meyer ([email protected]),

wetenschappelijke secretaresse van de BVK, vóór 30 November 2016.

De kandidaturen dienen vergezeld te zijn van een curriculum vitae.

Tweejaarlijkse Prijs ter ondersteuning van een

Wetenschappelijk Onderzoeksproject van de BVK/SBP

http://bvksbp.be/


Een prijs ter waarde van € 20.000 zal toegekend worden tijdens

het jaarlijkse congres van de BVK in Maart 2017 aan

de auteur van een onderzoeksproject op het vlak van

kindergeneeskunde. Het project moet gepland worden

in samenspraak met een Belgische universiteit en bijdragen tot de

ontwikkeling van de kindergeneeskunde in België.

Het reglement is beschikbaar op de site van de

Belgische Vereniging voor Kindergeneeskunde (www. bvksbp.be).

De scripties moeten elektronisch gestuurd worden naar Mevrouw

Anne-France De Meyer ([email protected]),

wetenschappelijke secretaresse van de BVK, vóór 30 November 2016.

De kandidaturen dienen vergezeld te zijn van een curriculum vitae.





1. Een prijs ter waarde van € 20.000 zal toegekend worden tijdens het jaarlijkse congres van de de BVK in maart 2017 aan de auteur van een onderzoeksproject op het vlak van kindergeneeskunde bekronen. Het Project moet gerealiseerd worden in samenspraak met een Belgische universiteit en bijdragen tot de ontwik-keling van de Kindergeneeskunde in België.

2. De kandidaten moeten kinderartsen zijn of assistenten in kindergeneeskunde, leden van de BVK en, sinds minder dan 10 jaar, gediplomeerde artsen op het ogenblik van het indienen van de kandidatuur.

3. Een wetenschappelijke commissie, bestaande uit een evenredig aantal leden van het Bureau van de BVK en experten van Europese Verenigingen voor Kindergeneeskunde, zal de kandidaturen beoordelen. Dit zal gebeuren binnen de maand na ontvangst van de aanvragen. Zij zullen zich zowel uitspreken over de wetenschappelijke waarde van de ingediende projecten als over hun uitvoerbaarheid en de relevantie van de kosten.

4. De richtlijnen zullen, vanaf Oktober te vinden zijn op de website van de BVK (www.bvksbp.be).

5. De elektronisch ingevulde aanvragen moeten gestuurd worden naar Mevrouw Anne-France De Meyer ([email protected] ), wetenschappelijke secretaresse van de BVK/SBP, voor 30 November 2016. De aanvragen moeten in het Engels opgesteld zijn. De kandidaturen dienen vergezeld te zijn van een curriculum vitae.

6. Het Project mag gecumuleerd worden met één of meerdere andere financieringsbronnen.

7. Het Project mag tot 2 maal ingediend worden bij de wetenschappelijke commissie.

8. Bij gebrek aan kandidaturen of indien het niveau van de ingediende werken wetenschappelijk onvoldoende blijkt te zijn, is de BVK vrij te beslissen de prijs niet toe te kennen.

9. De ingestuurde werken zullen voorgesteld worden op het jaarlijks congress in de Sessie “Jonge onderzoe-kers”.

10. De Winnaar van de prijs zal bekend worden tijdens het congress. Het is absoluut noodzakelijk dat de laureate aanwezig zijn tijdens de proclamatie met het oog op de van de prijs.

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Round Table “Fat and Child’s brain”.

Article

IntroductionThe Belgian Society of Paediatrics (BSP) is committed to promote children’s health through its several actions directed towards paediatricians including those post-graduates in training but also towards general practitioners and public health officers and agents in relation with children. Our communication is conveyed through this journal, note its new denomination, Belgian Journal of Paediatrics, (BSP) but also through the professional section of our website www.bvksbp.be Other actions are directly addressed to the general public, especially parents, using several channels such as information leaflets in display in hospitals and private practice offices and also through the public section of our website.The five main pilars of our very important topics commitments for children’s public health, are regularly studied and published through our different media:

1. Fluids and hydratation, 2. Nutrition,3. Hygiene 4. Prevention and vaccines, 5. Instrumental and psychological development

In order to diversify our information channels, the BSP decided to organize several round tables concerning our main goals. Each round table will comprise lectures by experts followed by discussions moderated by a prestigious expert in the field,

The role of the discussion is to clarify and develop some aspects of the lectures in order to promote the understanding of specialised and complex concepts by our readers, our members and all those interested in children’s health.

The first Round table “Fat and child’s brain” has been held on May 19 and was devoted to explore different aspects of the role of lipids on the development of the brain in the neonate and to illustrate some of the diseases due to distortions of fat metabolism and how to address them. The audience was composed by invited participants who are themselves experts in the field or represent insitutions active in paediatrics or official institutions involved in public health.

I would like to express special thanks to our moderator, Professor Philippe Goyens for his help and perfect handling in our two national languages of this very successful first BSP’s Round Table and also to Dr Marie-Françoise Reynebeau who has very accurately written the report.

Professor Samy Cadranel, coordinator of the round table.

ProgramModérator Prof. Philippe Goyens, ULB-VUB, Paediatrician, Nutrition and MetabolismSpeakers Dr Luc Regal, UZ Brussel & HUDERF-ULB, Neurologist Dr Thibault Senterre, CHR Citadelle Liège, NeonatologistCoordinator Prof. S. Cadranel, member of the board of BSP and chief editor of BJP18:00 -18:30 Welcome address18:30 -18:35 Pr Ph Goyens Introduction 18:35 -19:00 Dr L Regal Role of fat in paediatric neurometabolic diseases19:00 -19:25 Dr Th Senterre Role of fat in neonatal nutrition and metabolism19:25 - 20:00 Pr Ph. Goyens Discussion

ParticipantsDr Alexandra Bobarnac, Paediatric gastroenterologist , CHC Montegnée, Liège

Dr Olivia Bauraind, Paediatric gastroenterologist, CHC Montegnée, Liège,

Dr.Nicolas Deconinck, Neuropaediatrician, HUDERF-ULB

Dr Ann De Guchetenaere, Paediatrician, Head of Zeepreventorium De Haan, President of VVK

Mevr Karin Delanghe, Chief-dietitian UZBrussel, Representing VBVD

Dr Nadine De Ronne, Paediatrician, representing Kind en Gezin,

Mrs Laurence Doughan, Federal Ministry of Public Health

Dr Jean Paul Langhendries, Neonatologist, CHC Rocourt Liège, member of GBPF

Mrs Martine Robert, Chief-dietitian HUDERF-ULB, President of CEDE

Dr Michèle Scaillon, Paediatric gastroenterologist HUDERF-ULB, past president of BeSPGHAN

Prof. Françoise Smets, Paediatric gastroenterologist, UCL, past-president of BeSPGHAN

Dr. Jean P§ierre Van Biervliet, Past-head of department of Paediatrics St Jan Ziekenhuis Brugge,

Prof. Yvan Vandenplas, Head of Department of Paediatrics, UZ Brussel member of VVK

Mrs. Lut Van Lierde, Dietitian

Dr Genevieve Veereman, Paediatric gastroenterologist, UZ Brussel, KCE, member of VVK

Dr Laurence Waroquier, Paediatrician, representing ONE, member of GBPF

Dr M-F. Reneybeau, writer in charge of the report in BJP



De rol van lipiden bij pediatrische neurometabole aandoeningen. Dr Luc Régal.

HUDERF en UZ Brussel.

[email protected]

Inleiding

Lipiden zijn stoffen van biologische oorsprong die goed oplosbaar zijn in organische oplosmiddelen en moeilijk of niet oplosbaar zijn in water.

De vetcomponent van lipiden kan opgebouwd zijn uit twee soorten bouwstenen: keto-acylgroepen die vetzuren vormen enderzijds en isoprenen die sterolen vormen anderzijds. Lipiden kunnen ook een component bevatten die geen vet is. Het meest gekend is glycerol, dat in combinatie met vetzuren de triglyceriden vormt. Vetzuren, sterolen en triglyceriden worden beschouwd als eenvoudige lipiden.

Complexe lipiden bevatten nog andere componenten of modificaties, zoals glutathion, serine, fosfaat, sacchariden, siaalzuur, inositol, eiwitten. Deze combinaties leiden tot bijvoorbeeld tot fosfolipiden, etherfosfolipiden, sfingolipiden, en eiwitten met een lipidemodificatie 1.

Eenvoudige en complexe lipiden spelen onder andere een rol in de samenstelling van membranen, celstructuur, membraanverankering van eiwitten, intracellulair transport, energiemetabolisme, endocriene functies, signalisatie, en als cofactor bij andere metabole processen zoals het aminozuurmetabolisme, glycosylatie en de respiratoire keten. Er zijn meer dan 100 stofwisselingsziekten beschreven die veroorzaakt worden door een defect in één van de vele enzymen betrokken in het lipidenmetabolisme. In deze bijdrage geven we een kort overzicht van enkele van de neurologische aandoeningen binnen deze groep stofwisselingsziekten.

A. Eenvoudige lipiden

1) Vetzuren en triglyceriden

Er zijn metabole defecten van de vetzuurafbraak en van de vetzuursynthese. Daarnaast zijn er defecten bekend in de afbraak en aanmaak van triglyceriden. In de vetzuurafbraak onderscheiden we de carnitinecyclus, de mitochondriale β-oxidatie, het ketonlichaammetabolisme, en de peroxisomale α-en β-oxidatie.

Mitochondriale β-oxidatie en carnitinecyclusDe functie van de mitochondriale β-oxidatie is productie van energie, vooral in periodes van vasten. (Figuur 1) toont een vereenvoudigd schema van de mitochondriale oxidatie van lange-keten vetzuren (Long Chain Fatty Acid, LCFA). Wanneer deze vetzuren de cel binnenkomen worden ze in het cytoplasma gekoppeld aan co-enzym A (CoA). Er een specifiek transportsysteem nodig om de vetzuren binnen te brengen in de mitochondriën. Eerst vervangt CPT1 (carnitine palmitoyl transferase 1) CoA door carnitine, vervolgens transporteert CAT (carnitine acylcarnitine translocase) het vetzuur dat gebonden is aan carnitine tot in de mitochondria, en tenslotte vervangt CPT2 (carnitine palmitoyl transferase 2) carnitine terug door CoA voor de verdere reacties van de β-oxidatie.

Figuur 1²

De best gekende defecten in de context van de mitochondriale β-oxidatie zijn defecten van enzymen die de vetzuurafbraak zelf uitvoeren (figuur 2), met name medium-chain acyl- CoA dehydrogenase deficiëntie of MCAD deficiëntie, very-long-chain acyl- CoA dehydrogenase deficiëntie of VLCAD deficiëntie, mitochondriaal trifunctioneel enzyme (MTP) deficiëntie. Deze aandoeningen, evenals de defecten in de carnitinecyclus, worden allemaal gekenmerkt door hypoglycemie bij katabole situaties, wat secundair kan leiden tot neurologische sequellen. VLCAD deficiëntie, MTP deficiëntie en CPT2 deficiëntie kunnen bovendien aanleiding geven tot rhabdomyolyse. Bij MTP deficiëntie zien we ook een progressieve polyneuropathie, en bij de neonatale vorm van CPT2 deficiëntie zijn er cerebrale atrofie en corticale aanlegstoornissen (polymicrogyrie) ³.

Figuur 2

Een recenter ontdekt defect is deficiëntie van short-chain enoyl-CoA hydratase, door een mutatie van het ECHS1 gen, dat tussenkomt in de 2e stap

Article



Article

van de mitochondriale β-oxidatie (Figuur 2). Dit leidt tot het optreden van een Leigh syndroom-achtig beeld: groeiachterstand, hypotonie, dystonie, ataxie, ontwikkelingsachterstand, gehoorverlies, opticusatrofie en nystagmus. MRI van de hersenen toont letsels ter hoogte van het putamen en de MR spectroscopie toont een lactaatpiek. Dit klinisch beeld wordt wellicht mede bepaald door de rol die dit enzym speelt in het metabolisme van vertakte keten aminozuren (valine) 4-6.

Defecten in het metabolisme van de cofactoren die nodig zijn voor de mitochondriale β-oxidatie kunnen bovendien ook aanleiding geven tot neurometabole aandoeningen. We overlopen kort problemen in carnitinemetabolisme, metabolisme van CoA en defecten in ETF (electron transfer flavoprotein).

De endogene synthese van carnitine kan deficiënt zijn. Onlangs werd een verband aangetoond tussen een tekort aan trimethyllysine deoxygenase, dat noodzakelijk is voor de biosynthese van carnitine, en autisme 7, 8.

Neurologische problemen kunnen ook geassocieerd zijn met defecten in verschillende stappen van de synthese van CoA (figuur 3) 9. CoA speelt een centrale rol in zeer veel metabole processen en de gevolgen van deze defecten zijn dus ruimer dan enkel verstoring van de vetzuuroxidatie.

Figuur 3

Pantothenaat kinase 2 deficiëntie (te wijten aan een mutatie van het PANK2 gen) veroorzaakt PKAN (pantothenate kinase-associated neurodegeneration), een vorm van neurodegeneratie met ijzerstapeling in de hersenen (NBIA, neurodegeneration with brain iron accumulation). De symptomen zijn progressieve dystonie, spasticiteit, retinopathie, achteruitgang van de cognitieve functies; de kinderen overlijden meestal in de eerste 20 jaar van hun leven. Vormen met begin op volwassen leeftijd gekenmerkt door parkinsonisme en psychiatrische stoornissen zijn beschreven. Op de cerebrale MRI beelden zien we in de globus pallidus het klassieke teken van “eye of the tiger”: hyperintensiteit van de centrale regio omgeven door een hypo-intense ring op T2 gewogen beelden.

Deficiëntie van CoA synthase, het enzym dat betrokken is bij de 2 laatste stappen van de synthese van CoA, leidt ook tot NBIA, met een vergelijkbaar fenotype als PKAN maar zonder retinopathie 10.

In geval van ETF of ETF-QO deficiëntie (figuur 1) spreekt men van multipel

acyl-CoA dehydrogenase deficiëntie (MADD, multiple acyl-CoA dehydrogenase deficiency). ETF is nodig voor de regeneratie van FAD+, een cofactor voor de verschillende acyl-CoA dehydrogenasen, en ETF deficiëntie leidt bijgevolg tot een defect in multipele acyl-CoA dehydrogenasen. Het klinisch beeld is variabel: deze kinderen hebben, afhankelijk van de ernst van het fenotype, cardiomyopathie, myopathie, alsook metabole decompensaties. Er bestaat een ernstige neonatale vorm met cerebrale afwijkingen zoals geobserveerd bij CPT2 deficiëntie. Progressieve leuko-encefalopathie kan optreden 11.

KetonlichaammetabolismeDe mitochondriale β-oxidatie leidt tot de vorming van acetyl-CoA. In de lever wordt dit omgezet in hydroxymethylglutaryl-CoA (HMG-CoA) door HMG-CoA synthase. Onder invloed van HMG-CoA lyase, wordt HMG-CoA omgezet in aceto-acetaat dat in evenwicht staat met β -hydroxybutyraat. Deze 2 ketonlichamen komen terecht in het bloed (figuur 4).In de andere organen moet aceto-acetaat vervolgens opnieuw gekoppeld worden aan CoA door SCOT (succinyl-CoA keto-acid-CoA transferase). Vervolgens wordt het gesplitst door het thiolase T2 , wat leidt tot acetyl-CoA dat kan gebruikt worden in de Krebs cyclus en zo energie oplevert.

Figuur 4

De cerebrale gevolgen van stoornissen in het metabolisme van de ketonlichamen kunnen secundair zijn aan hypoglycemie, zoals bij stoornissen van de vetzuuroxidatie. In geval van stoornissen in de ketolyse kan bovendien een ernstige ketoacidose optreden, die fataal kan zijn. Bij HMG-CoA lyase deficiëntie zien we mentale retardatie, epilepsie, en leuko-encefalopathie. T2 deficiëntie kan gepaard gaan met ataxie, letsels van de basale ganglia en ontwikkelingsachterstand 12.

Peroxisomale α- en β-oxidatieIn de peroxisomen worden de extra-lange-keten vetzuren en de vetzuren met vertakte keten afgebroken. Tijdens de galzuursynthese gebeurt er ook α- en β-oxidatie van een zijketen in de peroxisomen. Men onderscheid defecten in individuele peroxisomale enzymen en defecten in de biogenese van de peroxisomen als organel. De peroxisomen hebben veel metabole functies buiten het vetzuurmetabolisme. Bij de defecten in peroxisomale biogenese zijn er daarom ook metabole afwijkingen buiten het vetzuurmetabolisme 13.


Article

De belangrijkste stoornissen in individuele peroxisomale enzymen zijn: - De ziekte van Refsum wordt veroorzaakt door een stoornis in de α-oxidatie

van fytaanzuur. De symptomen zijn ichtyose, doofheid, retinopathie, polyneuropathie en ataxie. Ze begint meestal in de 2e levensdecade.

- X-gebonden adrenoleukodystrofie is geassocieerd met een stoornis in de transporters van de extra-lange-keten vetzuren in de peroxisomen. De pediatrische cerebrale vorm van deze ziekte presenteert zich onder de vorm van acute inflammatoire cerebrale demyelinisatie. Klinisch zijn er progressieve cognitieve problemen en spasticiteit, met fataal verloop tenzij er vroegtijdig stamceltransplantatie gebeurt. Een latere vorm manifesteert zich onder de vorm van myelopathie en polyneuropathie. Bij bepaalde personen zien we alleen bijnierschorsinsufficiëntie. Gezien deze ziekte X-gebonden is is genetische counseling van de ruimere familie aangewezen.

- D-bifunctional protein deficiëntie (D-BP deficiëntie) is een aandoening die de β-oxidatie van de extra-lange-keten vetzuren treft. Het klinisch beeld lijkt op het syndroom van Zellweger, waarbij de peroxisomale biogenese defect is.

Bij een peroxisomale biogenese stoornis zijn alle peroxisomale functies verstoord. Het prototype van deze groep van aandoeningen is het Zellweger syndroom. Dit wordt gekenmerkt door cerebrale dysgenese, epilepsie, afwezigheid van ontwikkeling, aantasting van lever en nieren, botafwijkingen, dysmorfie en overlijden in het eerste levensjaar. Er werden echter ook mildere vormen ontdekt en daarom spreekt men tegenwoordig over het Zellweger spectrum. Aan het mildste eind van het spectrum zijn er kinderen met normale mentale ontwikkeling en geïsoleerde neurologische (bv ataxie) of sensorische (bv retinopathie) beperkingen 14.

Synthese- en elongatiedefectenGecombineerde Malonacidurie en methylmalonacidurie, wordt veroorzaakt door mutaties in ACSF3. ACSF3 codeert voor een mitochondriaal acyl-CoA synthase dat specifiek werkt op malonzuur en methylmalonzuur. Het koppelen van malonzuur aan CoA is de eerste stap van de mitochondriale vetzuursynthese. De symptomen zijn variabel, maar hypoglycemie, intellectuele handicap, axiale hypotonie, epilepsie en episodes van metabole decompensatie met keto-acidose werden beschreven 15, 16.

Malonacidurie, veroorzaakt door Malonyl-CoA decarboxylase deficiëntie, wordt gekenmerkt door metabole decompensaties, hypotonie, encephalopathie, intellectuele handicap en cardiomyopathie. De pathofysiologie wordt onvolledig begrepen. Malonyl-CoA dehydrogenase catalyseert de reactie van malonyl-CoA naar acetyl-CoA in het cytoplasma en regelt zo de concentratie van malonyl-CoA, in het cytoplasma. Aangezien malonyl-CoA CPT1 inhibeert is er een verminderde β-oxidatie bij verhoging van de concentratie van malonzuur 17.

ELOVL (Elongation of very long chain fatty acids protein) 4 en 5 deficiëntie veroorzaken spinocerebellaire ataxie type 34 en 38 18, 19.

Defecten in het triglyceridenmetabolismeNeutral Lipid Storage Disease, NLSD, is een groep van aandoeningen met gestoorde afbraak van triglyceriden in het cytoplasma. Men onderscheidt NLSD met ichtyose (ziekte van Chanarin-Dorfman), veroorzaakt door mutaties in CGI-58 en Neutral Lipid Storage Myopathy, veroorzaakt door mutaties in ATGL. ATGL codeert voor het triacylglycerol lipase in de adipocyten, en CGI-58 is de activator van dit lipase. De ziekte van Chanarin-Dorfman wordt gekenmerkt door myopathie, ichtyose, intellectuele handicap, gehoordsdaling, cataract, ataxie, spasticiteit, cardiomyopathie en leversteatose. Bij neutral lipid storage myopathie staan de myopathie en de cardiomyopathie op de voorgrond. Verschillende andere defecten zijn beschreven 20.

In de lysosomen worden ook triglyceriden afgebroken, door lysosomal acid lipase (LAL). Deficiëntie van dit enzyme veroorzaakt Wolman disease en cholesteryl ester storage disease. Recent werd de efficiëntie van enzym vervangende therapie bij deze aandoeningen beschreven. Zonder behandeling is de ziekte van Wolman fataal onder de leeftijd van 1 jaar. Bij cholesteryl ester storage disease is er een verhoogd cardiovasculair risico, met eventueel secundair neurologische gevolgen 21, 22.

2) Sterolen

Sterolen zijn opgebouwd uit isopreen-eenheden. De aanmaak van sterolen loopt via een lange en complexe pathway, waarin meerdere defecten beschreven zijn.

Mevalonacidurie en hyperIgD syndroom zijn te wijten aan deficiëntie van mevalonaat kinase (MVK), in het begin van de biosynthese van cholesterol. Mevalonacidurie wordt enerzijds gekenmerkt door cyclische koortsepisodes met lymphadenopathie, braken, buikpijn, hepatosplenomegalie, gewrichtspijn en huiduitslag. Anderzijds is er intellectuele handicap, dysmorfie, ataxie, hypotonie, failure to thrive, en een belangrijk risico op vroegtijdig overlijden. Bij het mildere hyperIgD syndroom zijn er enkel de cyclische inflammatoire episodes.

Het Smith–Lemli–Opitz syndroom (SLOS) is te wijten aan deficiëntie van 7-dehydrocholesterol reductase, met een defecte cholesterolsynthese tot gevolg. Klinisch is er dysmorfie, genitale afwijkingen, syndactylie, intellectuele handicap en groeiachterstand. Verschillende andere defecten in de cholesterolsynthese en galzuursynthese werden beschreven 23.

B.Complexe lipidenBepaalde sterolen, leukotriënen, fosfolipiden, etherfosfolipiden, sfingolipiden worden meestal gerekend tot de complexe lipiden. Bijkomend zijn er de lipidenmodificaties van eiwitten. We zullen kort enkele van deze groepen overlopen en dan voorbeelden geven van defecten in lipidenmodificaties van eiwitten.

1. Dolichol is een sterol dat dient als drager van monoacchariden en oligosacchariden tijdens de glycosylatie. De defecten in dolicholsynthese veroorzaken daardoor glycosylatiestoornissen (CDG, congenitale stoornis van de glycosylatie). De defecten in dolicholsynthese gaan meestal gepaard met ontwikkelingsachterstand. Afhankelijk van het defect kan er epilepsie zijn, evenals ataxie, visusverlies, spierdystrofie, cardiomyopathie en/of ichtyose 24.

2. Co-enzym Q10 is een ander sterol, dat dient voor het elektronentransport tussen enerzijds complex I en II, en anderzijds complex III van de mitochondriale respiratoire keten. Verder is het een cofactor voor ETF-metabolisme, in de pyrimidine synthese, en is het een belangrijk anti-oxidans. Verschillende defecten in de biosynthese van co-enzym Q10 veroorzaken daardoor een mitochondriale aandoening. Toediening van co-enzyme Q10 kan het verloop van deze ziekten gunstig beïnvloeden 25.

3. Deficiëntie van Leukotrieen C4 synthese veroorzaakt een ernstige ziekte met uitgesproken hypotonie, ontwikkelingsachterstand, microce-falie en vroegtijdig overlijden. Mogelijk wijst dit erop dat leukotrieen C

4

ook een rol heeft als neuromodulator of messenger in de hersenen 26.4. Defecten in het metabolisme van cardiolipine veroorzaakt door mutaties

in tafazzin, zijn de oorzaak van het Barth syndroom. Cardiolipine is een fosfolipide gelocaliseerd in de interne mitochondriale membranen, en het Barth syndroom is een mitochondriale aandoening. De belangrijkste ken-merken zijn myopathie, cardiomyopathie, neutropenie. Verschillende an-dere defecten in fosfolipidenmetabolisme werden recent beschreven 27.

http://eiwitten.we/


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5. De stoornisssen in de synthese van plasmalogenen (etherfosfolipiden) veroorzaken Rhizomelic Chondrodysplasia Punctata (RCDP), waarvan tot nu toe 5 types werden beschreven. De getroffen kinderen hebben een intellectuele handicap, doofheid, retinopathie, rhizomelie, en ichtyose 28, 29.

6. Er kunnen stoornissen in de synthese van de sfingolipiden (die onder andere leiden tot een vorm van epilepsie) of hun afbraak voorkomen. Defecten in de afbraak zijn verantwoordelijk voor goed bekende aandoeningen zoals de ziekte van Fabry en de ziekte van Gaucher 30.

7. Lipidenmodificaties van eiwitten

Bepaalde lipiden zijn gekoppeld aan eiwitten als cofactor voor hun enzymatische werking, zoals bijvoorbeeld liponzuur. Andere lipiden binden aan eiwitten zodat deze zich aan membranen kunnen hechten met behulp van dit lipidenanker.

Niet-ketotische hyperglycinemie is te wijten aan defecten in het glycine cleavage systeem. Deze aandoening wordt gekenmerkt door neonatale hypotonie, epilepsie, hikken, respiratoir falen en meestal overlijden in de neonatale periode. Kinderen die door neonatale intensieve zorgen de neonatale periode overleven hebben een vrijwel afwezige mentale ontwikkeling. Nochtans zijn er ongeveer 10% van de kinderen met niet-ketotische hyperglycinemie die een minder ernstige presentatie hebben en die een variabele graad van ontwikkeling bereiken. Liponzuur, een hydrofobe molecule afgeleid van een C8 vetzuur, wordt gebonden aan de H-subunit van het glycine cleavage systeem en is hiervoor een essentiële cofactor. Daarnaast is liponzuur ook een cofactor voor het pyruvaat dehydrogenase complex, het alfa-ketoglutaraat dehydrogenase complex, het vertakte keten ketozuur dehydrogenase (BCKDH) en 2-oxoadipaat dehydrogenase. Defecten in de synthese van liponzuur (mutaties in LIAS) veroorzaken dan ook een variant van niet-ketotische hyperglycinemie 31.

IJzer-zwavel clusters zijn noodzakelijk als zwaveldonoren in de biosynthese van liponzuur. Ijzer-zwavel clusters zijn echter ook essentieel in talrijke andere metabole processen, onder andere in complexen I, II, en III van de mitochondriale respiratoire keten. Mutaties in genen die betrokken zijn bij het metabolisme van de ijzer-zwavel clusters: NFU1, BOLA3 en GLRX5 veroorzaken daarom een nog bredere waaier van enzymatische defecten, met een combinatie van niet-ketotische hyperglycinemie en mitochondriale dysfunctie 32-34.

Verschillende defecten werden beschreven in de synthese van glycofosfatidylinositol (GPI) ankers. Deze worden gehecht aan eiwitten zodat deze zich aan de celmembraan kunnen hechten. Defecten in deze synthese, die ook tot de groep van glycosylatiestoornissen behoren, geven aanleiding tot verschillende ziektebeelden, meestal gepaard gaand met intellectuele handicap 35.

Palmitoylering is ook een modificatie van eiwitten die hun localisatie ter hoogte van membranen mogelijk maakt. Verschillende enzymen zorgen voor het aanhechten en andere voor het terug losmaken van het palmitaat (C16 vetzuur), en bepalen zo of een eiwit zich ter hoogte van membranen of in het cytoplasma bevindt. Dit proces wordt beïnvloed door hormonen, en speelt zo een rol in signalisatie. Talrijke neuronale eiwitten, onder andere in de synaps, zijn gepalmitoyleerd. Een voorbeeld van een defect in palmitoylering is het 22q11 deletiesyndroom of velocardiofaciaal syndroom. zDHHC8, dat codeert voor een palmitoylerend enzym, is betrokken in de deletie, en studies van een muismodel suggereren dat deficiëntie van dit enzym verantwoordelijk is voor de cognitieve en psychiatrische problemen bij deze patiënten 36, 37.

ConclusieLipiden vervullen talrijke essentiële functies voor het zenuwstelsel. Er zijn dan ook talrijke defecten in het lipidenmetabolisme die neurologische gevolgen hebben. De stoornissen in het metabolisme van de complexe lipiden zijn een relatief recent ontdekte groep die snel groter wordt. Bepaalde van deze stoornissen hebben rechtstreekse impact op zeer verscheiden metabole routes, waardoor 1 defect kenmerken kan combineren van verschillende klassieke metabole aandoeningen.

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6. Tetreault M, Fahiminiya S, Antonicka H, et al. Whole-exome sequencing identifies novel ECHS1 mutations in Leigh syndrome. Hum Genet. 2015 Sep;134(9):981-91.

7. Celestino-Soper PB, Violante S, Crawford EL, et al. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism. Proc Natl Acad Sci U S A. 2012 May;109(21):7974-81.

8. Ziats MN, Comeaux MS, Yang Y, et al. Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation. Am J Med Genet A. 2015 Sep;167A(9):2162-7.

9. Daugherty M, Polanuyer B, Farrell M, et al. Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. J Biol Chem. 2002 Jun;277(24):21431-9.

10. Colombelli C, Aoun M, Tiranti V. Defective lipid metabolism in neurodegeneration with brain iron accumulation (NBIA) syndromes: not only a matter of iron. J Inherit Metab Dis. 2015 Jan;38(1):123-36.

11. Van Hove JL, Grünewald S, Jaeken J, et al. D,L-3-hydroxybutyrate treatment of multiple acyl-CoA dehydrogenase deficiency (MADD). Lancet. 2003 Apr;361(9367):1433-5.

12. Fukao T, Mitchell G, Sass JO, Hori T, Orii K, Aoyama Y. Ketone body metabolism and its defects. J Inherit Metab Dis. 2014 Jul;37(4):541-51.

13. Waterham HR, Ferdinandusse S, Wanders RJ. Human disorders of peroxisome metabolism and biogenesis. Biochim Biophys Acta. 2016 May;1863(5):922-33.

14. Régal L, Ebberink MS, Goemans N, et al. Mutations in PEX10 are a cause of autosomal recessive ataxia. Ann Neurol. 2010 Aug;68(2):259-63.

15. Alfares A, Nunez LD, Al-Thihli K, et al. Combined malonic and methylmalonic aciduria: exome sequencing reveals mutations in the ACSF3 gene in patients with a non-classic phenotype. J Med Genet. 2011 Sep;48(9):602-5.

16. Sloan JL, Johnston JJ, Manoli I, et al. Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria. Nat Genet. 2011 Sep;43(9):883-6.

17. Prada CE, Jefferies JL, Grenier MA, et al. Malonyl coenzyme A decarboxylase deficiency: early dietary restriction and time course of cardiomyopathy. Pediatrics. 2012 Aug;130(2):e456-60.

18. Ozaki K, Doi H, Mitsui J, et al. A Novel Mutation in ELOVL4 Leading to Spinocerebellar Ataxia (SCA) With the Hot Cross Bun Sign but Lacking Erythrokeratodermia: A Broadened Spectrum of SCA34. JAMA Neurol. 2015 Jul;72(7):797-805.

19. Di Gregorio E, Borroni B, Giorgio E, et al. ELOVL5 mutations cause spinocerebellar ataxia 38. Am J Hum Genet. 2014 Aug;95(2):209-17.

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Les graisses dans la nutrition néonatale. Thibault Senterre.

CHU de Liège.

[email protected]

Introduction

Les graisses de l’alimentation ont souvent considérées comme étant principalement des nutriments à haute densité énergétique. Néanmoins, elles représentent également une source d’acides gras essentiels au métabolisme humain. C’est le cas de l’acide linoléïque (linoleic acid, LA, C18 :2n-6) et de l’acide alpha linolénique (alplha-linolenic acid, ALA, C18 :3n-3). Ces deux acides gras essentiels permettent ensuite la synthèse par élongation d’autres acides gras polyinsaturés à longue chaine (long-chain polyunsaturated fatty acids, LC-PUFAs) dont l’acide arachidonique (arachidonic acid, AA, C20 :5n-6), l’acide pentaénoique (eicosapentaenoic acid, EPA, C20 :5n-3) et l’acide docosahexaénoique (docosahexaenoic acid, DHA, C22 :6n-3). Ces LC-PUFAs sont indispensables au bon métabolisme des eicosanoïdes, des prostaglandines et de toute une série de médiateurs de l’inflammation. Ils sont aussi essentiels à l’intégrité de nombreuses membranes cellulaires. En 1992, M. Martinez démontrait la grande accumulation de DHA au niveau du tronc cérébral chez les fœtus et chez les nourrissons durant les premiers mois de la vie 1 (Fig1).

Fig 1



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Dans le système nerveux central, le DHA est incorporé de façon préférentielle dans les membranes cellulaires du cerveau et de la rétine. Il est nécessaire à un développement neurologique normal car il est utilisé dans la neuro-transmission dopaminergique. Il joue un rôle très important dans le fonctionnement de la rétine par l’activation de la rhodopsine, et dans la transmission de l’influx visuel vers le cerveau.

Des études sur des modèles animaux ont montré qu’un déficit nutritionnel important en n-3 LC-PUFAs altérait significativement le développement des neurones avec une diminution secondaire sévère de l’acuité visuelle et des troubles du développement cognitif qui pouvaient être en partie réversibles en cas de correction des apports en DHA 2.

L’accumulation fœtale durant le 3ème trimestre de la gestation en LC-PUFAs est estimée à 106 mg/kg/j de LA, 212 mg/kg/j d’ARA, 4 mg/kg/j d’ALA et 43 mg/kg/j de DHA 3. On sait également qu’il existe transfert placentaire sélectif de DHA par rapport aux autres LC-PUFAs. Ceci a donc de grandes conséquences potentielles pour les nouveau-nés prématurés chez qui le transfert placentaire est interrompu et chez qui les réserves corporelles en graisse sont très faibles. En effet, la masse grasse d’un grand prématuré de 24 semaines de gestation est d’environ 1% contre 12-15% à terme. De plus, il est reconnu que les fœtus ont des capacités de synthèse limitées de ces LC-PUFAs en raison d’une capacité enzymatique insuffisante par rapport à la déposition théorique attendue.

Très récemment, une étude observationnelle a montré que des apports précoces élevés en DHA étaient associés à moins de risques d’hémorragies cérébrales chez les grands prématurés et que l’augmentation des taux sanguins en DHA associée à des valeurs basses en LA étaient associées à une meilleure évolution neuro-développementale 4.

Les graisses du lait humain se présentent généralement sous forme des globules lipidiques qui contiennent essentiellement des triglycérides (98%), et d’un peu de phospholipides (1%) et de cholestérol (0,5%). La concentration moyenne en lipides du lait maternel est d’environ 3,8 g/100 ml, ce qui fournit un peu moins de 50 % des apports énergétiques totaux du nouveau-né allaité. Cependant, il existe une très grande variabilité interindividuelle quant à la teneur et à la composition en graisses du lait. Cette variabilité dépend essentiellement de la localisation géographique de la population étudiée, du stade de la lactation, du terme de la gestation, du moment de la journée et du moment de la tétée. De plus il existe une très grande variabilité interindividuelle entre chaque femme allaitante qui dépend beaucoup du régime alimentaire de celle-ci. Cette variabilité influence grandement la teneur en LC-PUFAs du lait humain et plus particulièrement la teneur en ALA et DHA comparativement à LA et ARA qui sont plus stable. C’est ainsi que la proportion des graisses du lait humain peut varier entre 7,9 et 17,8% pour le LA, entre 0,45 et 2,0% pour l’ALA, entre 0,24 et 1,0% pour l’ARA et entre 0,06 et 1,4% pour le DHA. Cette variabilité dépend essentiellement du régime alimentaire de la femme allaitante 5.

L’absorption intestinale des graisses est généralement bonne mais est souvent plus faibles chez les prématurés (70- 80%) que chez les nouveau-nés à terme. En effet, la pasteurisation du lait inactive sa lipase qui est stimulée par les sels biliaire et elle modifie la structure de ses globules de graisse. De plus, chez les prématurés, le fait de la récolter le lait dans un récipient puis de le transvaser

dans d’autres récipients avant de pouvoir l’administrer via des sondes de gavages implique une adsorption des graisses sur les parois des récipients utilisés. Ceci ajoute donc une encore plus grande variabilité que la variabilité naturelle dans l’apport en graisses chez les prématurés nourris avec du lait humain.

Dans le lait humain, les LC-PUFAs sont surtout présents dans les triglycérides en position 2 ou 3 et parfois dans la fraction phospholipidique ce qui permet une bonne digestibilité. Par contre, dans les formules de lait industriel et dans les suppléments nutritionnels disponibles, les LC-PUFAs proviennent de différentes sources dont des algues (pas de spécificité de position du DHA dans les triglycérides) et des huiles de poisson (apports d’EPA et DHA en position 2), ce qui a aussi des conséquences sur leur biodisponibilité.

Besoins nutritionnels en DHA des prématurésLes prématurés sont très dépendant des apports nutritionnels en DHA en raison de leurs capacités de synthèse endogène limitées et de leurs très faibles réserves en graisses.

Il est difficile de définir les besoins exacts en DHA pour chaque enfant prématuré. Ceux-ci doivent permettent une croissance adéquate avec une composition optimale en DHA des différents tissus tout en optimisant le devenir à court, moyen et long terme. La référence utilisée est généralement l’évolution du fœtus sains durant sa vie intra-utérine puis celle-des nouveau-nés à terme allaités et en bonne santé. Cependant le métabolisme d’un fœtus in utero n’est pas tout à fait comparable avec celui d’un nouveau-né qui est soumis à des contraintes supplémentaire en terme de dépenses et donc de besoins.

Durant le 3e trimestre de la grossesse, la croissance des différents organes n’est pas proportionnelle au gain pondéral. De plus, la qualité du gain pondéral de chaque tissu varie également. En particulier, le gain en masse grasse et en tissu adipeux est particulièrement important avec un important dépôt de LC-PUFAs de type oméga-3 6 (Fig 2).

Fig 2


On sait à partir des modèles animaux qu’il existe une corrélation entre les taux sanguin en DHA et leurs concentrations cérébrales mais cette relation n’est pas linéaire. Cependant, chez les humains, il ne semble pas qu’il existe un seuil plasmatique de DHA en dessous duquel on peut définir une insuffisance pour le bon développement du cerveau 7.

Néanmoins, on sait que le taux sanguin en DHA des nouveau-nés prématurés est inférieur à celui des nouveau-nés à terme et que leurs taux sanguins lorsqu’ils arrivent à terme peut être encore plus bas si leurs apports ne sont pas enrichis en DHA 8. Une étude a mis en évidence que même si les apports en DHA augmentent en général au cours des 4 premières semaines de vie, ces apports restent en moyenne très nettement inférieurs aux besoins et à la déposition observée durant la vie intra-utérine qui est estimée 45 mg/kg/j 9. Ces apports insuffisant induisent donc un déficit cumulatif en DHA très significatif qui est corrélé négativement avec le poids à la naissance : plus le nouveau-né est petit, plus il présente un déficit cumulatif important en DHA (13). Ceci s’explique aussi par le fait que la composition des laits donnés aux prématurés ne permet pas d’atteindre des apports suffisants en LC-PUFAs et en particulier en DHA 10.

Les résultats des études cliniquesDe nombreuses études ont été réalisées pour évaluer l’intérêt des suppléments alimentaires en LC-PUFAs, et en particulier en DHA. Une méta-analyse récente a intégré 17 études randomisées dont 13 de bonne qualité 11. Ces suppléments se sont montré sûr et sans effets secondaires. Néanmoins, peu de bénéfices clairs à long terme ont pu être mis en évidence sur les fonctions visuelles, le développement neurologiques et sur la croissance. Cette conclusion présente quelques limites en raison des caractéristiques des études inclues dans cette méta-analyse. En effet, de grandes variabilités existaient quant aux techniques d’évaluation, aux schémas de supplémentation (quantité et qualité des LC-PUFAs/DHA) et aux caractéristiques des groupes contrôles. De plus, ces études incluaient surtout des nouveau-nés à terme et des prématurés en bonne santé et donc à plus faible risque de déficit.On peut aussi regretter que peu de ces études aient utilisé le statut sanguin en LC-PUFAs dans leurs analyses alors que celui-ci possède une bonne corrélation avec les bénéfices attendus sur les fonctions visuelles et le développement cérébral. Une évaluation précises des besoins réels n’a donc pu été réalisée.

Une analyse plus approfondie de trois études reprises dans cette méta-analyse suggère qu’une supplémentation avec des LC-PUFAs provenant de poisson semblaient pouvoir procurer plus d’avantage en termes de neurodéveloppement, que l’effet augmentait chez les grands prématurés et chez les garçons 12-14.

Peu d’études ont évalués des apports élevés en DHA chez des grands prématurés. Parmi celle-ci, une étude norvégienne chez des grands prématurés (≤30 semaines) a comparé l’impact d’un apport en DHA de 1,6% avec 1,3% d’ARA comparativement à un apport de 0,7 % avec 0,5% d’ARA à partir de la première semaine de vie jusqu’à la sortie de l’hôpital. A 6 mois d’âge corrigé, les scores de résolution de problèmes et de mémoire de reconnaissance étaient améliorés par rapport au groupe contrôle. A 20 mois d’âge corrigé, les scores de développement mental ne différaient pas de manière significative mais on observait une corrélation entre le taux plasmatique de DHA réalisé à la sortie et les scores de développement mental. De plus, les capacités d’attention étaient améliorées avec également une corrélation avec les taux plasmatiques de DHA à la sortie.

Une autre étude avec une fortification élevée en DHA (1% versus 0,3%) a été évaluée dans une cohorte australienne de grands prématurés nés entre 27 et 31 semaines de grossesse. Celle-ci fut débutée entre le 2ème et le 5ème jour de vie et s’est poursuivie jusqu’au terme théorique. L’acuité visuelle était similaire à 2 mois d’âge corrigé mais s’améliorait significativement à 4 mois d’âge corrigé. A 18 mois d’âge corrigé, les scores moyens de développement mental et psychomoteur ne montraient pas de différences sauf chez les prématurés avec un poids à la

1. Martinez M. Tissue levels of polyunsaturated fatty acids during early human development. J Pediatr. 1992; 120: S129-38.

2. McCann JC, Ames BN. Is docosahexaenoic acid, an n-3 long-chain polyunsaturated fatty acid, required for development of normal brain function? An overview of evidence from cognitive and behavioral tests in humans and animals. Am J Clin Nutr. 2005; 82: 281-95.

3. Lapillonne A, Jensen CL. Reevaluation of the DHA requirement for the premature infant. Prostaglandins Leukot Essent Fatty Acids. 2009 Aug-Sep; 81: 143-50.

4. Tam EW, et al. Early postnatal docosahexaenoic acid levels and improved preterm brain development. Pediatr Res. 2016; 79: 723-30.

5. Brenna JT et al. Am J Clin Nutr. 2007; 85 : 1457-64.

6. Reevaluation of the DHA requirement for the premature infant. Prostaglandins Leukot Essent Fatty Acids. 2009; 81: 143-50.

7. Kim HW et al. Regulation of rat brain polyunsaturated fatty acid (PUFA) metabolism during graded dietary n-3 PUFA deprivation. Prostaglandins Leukot Essent Fatty Acids. 2011; 85: 361

8. Lapillonne A et al. The use of low-EPA fish oil for long-chain polyunsaturated fatty acid supplementation of preterm infants. Pediatr Res. 2000; 48:835-41.

9. Lapillonne A et al. Postnatal docosahexaenoic acid deficiency is an inevitable consequence of current recommendations and practice in preterm infants. Neonatology. 2010; 98: 397-403.

10. Lapillonne A, O'Connor DL, Wang D, Rigo J. Nutritional recommendations for the late-preterm infant and the preterm infant after hospital discharge. J Pediatr. 2013; 162 : S90-100.

11. Schulzke SM et al. Long-chain polyunsaturated fatty acid supplementation in preterm infants. Cochrane Database Syst Rev. 201116;: CD000375.

12. Clandinin MT et al. Growth and development of preterm infants fed infant formulas docosahexaenoic acid and arachidonic acid. J Pediatr. 2005; 146: 461-8.

REFERENCES:

naissance inférieur à 1250 g et chez les filles qui bénéficiaient significativement du régime enrichi. De plus, un déficit sévère était moins fréquent dans le groupe enrichi. Par contre, plus aucun bénéfice n’a pu être documenté à 2 et 5 ans au niveau du langage et du comportement et à 7 ans au niveau des capacités cognitives et visuelles.

A côté des effets neurodéveloppementaux, il existe aussi des données qui suggère un effet bénéfique d’un enrichissement sur les fonctions respiratoires et sur la croissance staturale 15,16.

ConclusionsLes LC-PUFAS et le DHA en particulier sont des nutriments essentiels pour les fœtus et les nouveau-nés, tant pour le développement de leur cerveau et de leur vision que pour de nombreuses autres fonctions biologiques. La période périnatale est une période à risque de déficit. Les grands prématurés constituent une population particulièrement à risque et des déficits sont régulièrement documentés en raison des faibles apports qui sont observés avec les sources nutritionnelles actuelles.

Une supplémentation des mères pendant leur grossesse et leur allaitement doit être proposé. Il est ainsi conseillés aux mères qui allaitent de consommer un minimum de 200 mg par jour de DHA afin d’enrichir leur lait et des apports en graisses avec une proportion de DHA >1% est peut-être même souhaitable via un enrichissement complémentaire.

De nouvelles études avec des concentrations plus élevées en LC-PUFAs et en DHA jusqu’à trois fois les posologies actuelles sont à envisager tout en portant une attention particulière au rapport entre les différents LC-PUFAs, et notamment le rapport DHA/ARA.


Article

13. Fewtrell MS et al. Double-blind, randomized trial of long-chain polyunsaturated fatty acid supplementation in formula fed to preterm infants. Pediatrics. 2002; 110 (: 73-82.

14. Fewtrell MS et al. Randomized, double-blind trial of long-chain polyunsaturated fatty acid supplementation with fish oil and borage oil in preterm infants. J Pediatr. 2004 144: 471-9.

15. Collins CT, Makrides M, Gibson RA et al. Pre and post-term growth in pre-term infants sup-plemented with higher-dose DHA: a randomised controlled trial. Br J Nutr. 201;105:1635-43

16. Manley BJ, Makrides M, Collins CT et al., High-dose docosahexaenoic acid supplementation of preterm infants: respiratory and allergy outcomes. Pediatrics. 2011 ;128:e71-7.

Discussion. - Discussie.

A la suite des exposés plusieurs participants sont intervenus et la discussion, dirigée par le modérateur, a permis d’aborder une série de sujets en relation avec le thème.

Dosage des lipidesIl est en effet difficile, dans les études actuelles, de savoir quels lipides sont dosés : les phospholipides, les triglycérides ou les lipides totaux ? Pour les experts présents, ce dosage devrait se faire sur les membranes érythrocytaires, idéalement sur les membranes internes et externes, séparément. En effet, cette mesure donne une idée des concentrations sur le long terme, alors qu’un dosage dans le plasma est le reflet d’une situation ponctuelle.

Transport des acides gras au cerveauLes pathologies neurométaboliques sont des affections complexes, qui posent la question du transport des lipides au cerveau, un problème encore mal élucidé.lors qu’il existe un transporteur pour les corps cétoniques, il ne semble pas y en avoir pour les acides gras. Le flip-flop (mouvement de la membrane cellulaire) pourrait favoriser le passage des phospholipides dans le cerveau, où ils pourraient céder les chaînes longues. Mais il faut également tenir compte de l’existence de variations individuelles des nucléotides conduisant à la synthèse des acides gras à longue chaîne.

Supplémentations en acides gras Les données présentées sur l’efficacité de ces mesures mettent en évidence une réaction probablement différente dans des sous-groupes de nouveau-nés (dont les prématurés). La difficulté dans l’interprétation des résultats réside dans l’ajout de covariables (concentration des acides gras, métabolisation, etc.) qui interfèrent de manière importante sur le plan clinique et nutritionnel. La recherche devra définir les sous-groupes de nouveau-nés qui tireront le plus grand bénéfice d’une telle supplémentation en lipides. S’il semble qu’elle pourrait avoir un avantage en cas de bronchodysplasie, cela ne parait pas être le cas en ce qui concerne l’entérocolite ulcéronécrosante. L’hypothèse d’un rôle pro-inflammmatoire des acides gras n’a jamais été documentée, mais elle a engendré une limitation des apports, notamment en DHA, dans ce cas-là.Le problème de la supplémentation en acides gras est de définir la façon de la réaliser. Des études ont montré une chute des taux d’acide arachidonique chez des mères allaitantes supplémentées en DHA. Les voies enzymatiques conduisant à la synthèse de DHA et AA sont en effet compétitives. Les recommandations pour les prématurés concernant ces acides gras émises au début des années 2000 se sont concentrées sur des ratios. Aujourd’hui, on parle de quantités minimales à atteindre. Il reste cependant encore des éléments à définir comme les objectifs à atteindre

Naar aanleiding van de voordrachten, kwamen verschillende deelnemers tussen en de discussie, onder leiding van de moderator, bracht een aantal onderwerpen in verband met het thema aan het licht.

Dosering van de lipidenIn de huidige studies is het inderdaad moeilijk te weten welke lipiden gedoseerd zijn : de fosfolipiden, de triglyceriden of de totale lipiden? Volgens de aanwezige experts zou deze dosering moeten gebeuren op de erytrocytaire membraan, ideaal op de interne en de externe membraan afzonderlijk. Inderdaad, deze meting geeft een idee van de concentraties op lange termijn, terwijl een dosering in het plasma een momentopname is.

Transport van vetzuren in de hersenenNeurometabole aandoeningen zijn complexe aandoeningen die de kwestie stellen van het transport van lipiden in de hersenen, een probleem dat nog niet goed opgehelderd is. Terwijl er een transporter voor de ketonlichamen bestaat, lijkt er geen te bestaan voor de vetzuren. De flip-flop (beweging van de celmembraan) zou de passage van de fosfolipiden in de hersenen kunnen bevorderen, waar ze de lange ketens zouden afstaan. Maar men moet ook rekening houden met de aanwezigheid van individuele variaties in de nucleotiden die leiden tot de synthese van langeketenvetzuren.

VetzuursuppletiesDe gegevens die voorgesteld werden over de efficiëntie van deze maatregelen, tonen een wellicht andere reactie in subgroepen van pasgeborenen (waaronder prematuren). De moeilijkheid in de interpretatie van de resultaten ligt in de toevoeging van covariabelen (concentratie van vetzuren, metabolisatie enz.) die sterk interfereren op klinisch en nutritioneel vlak. Het onderzoek zal de subgroepen van pasgeborenen moeten definiëren die het meest baat zullen hebben bij een dergelijke suppletie van lipiden. Hoewel er een voordeel lijkt te bestaan in geval van bronchodysplasie, lijkt dit niet het geval te zijn bij necrotiserende enterocolitis. De hypothese van een pro-inflammatoire rol van de vetzuren werd nog nooit gedocumenteerd, maar ze heeft geleid tot een beperking van het aanbod, vooral aan DHA, in dit specifieke geval.Het probleem van de vetzuursuppletie bestaat erin te definiëren op welke manier ze moet gebeuren. Studies toonden een daling van de arachidonzuurspiegels bij zogende moeders die DHA suppletie kregen. De enzymatische pathways die leiden tot de synthese van DHA en arachidonzuur zijn immers competitief. De aanbevelingen voor prematuren in verband met deze vetzuren die gepubliceerd werden in begin van de jaren 2000, zijn gefocust op de ratio’s. Vandaag spreekt men van de minimaal te behalen hoeveelheden. Er moeten echter nog elementen gedefinieerd worden, zoals de doelstellingen die moeten gehaald worden.


Article

Malabsorptie van lipiden Bij alle syndromen van malabsorptie van lipiden, is het zeer belangrijk om supplementen, vitaminen,… te geven. Er bestaan weinig studies over het nut van lipidensuppletie in geval van mucoviscidose; in Scandinavië echter, wordt DHA systematisch toegediend via parenterale weg aan kinderen met mucoviscidose als ze gehospitaliseerd zijn, een maatregel die zeer duur is. In geval van ernstige cholestase krijgen kinderen met symptomen van deficit (zeer aanzienlijke huidletsels) lipidensuppletie, naast vitaminesuppletie. Maar dit is alleen van toepassing op zeer specifieke gevallen. Inderdaad, patiënten met ernstige cholestase krijgen een transplantatie op korte termijn en patiënten met matige cholestase zijn in staat om een zekere hoeveelheid lipiden te absorberen, die vaak wellicht voldoende is. De getransplanteerde kinderen hebben een blijkbaar normale neurologische en oftalmologische ontwikkeling. Er lijkt dus geen irreversibel of groot tekort aan lipiden te bestaan, hoewel de aantasting zeer vroegtijdig optreedt, zoals in geval van atresie van de galwegen bijvoorbeeld. Terwijl een proteïne- en energiesuppletie een beschermende rol kan spelen bij ernstige ischemische anoxie, werd dit niet beschreven voor de lipiden.

Peroxysomale ziekteAangezien de synthese van DHA gebeurt in de peroxysomen, hebben kinderen met een peroxysmale ziekte vaak een tekort aan DHA. Sommige studies – maar niet alle – tonen een gunstig effect van DHA-supplementen op het zicht bij deze kinderen wanneer ze langer overleven.

Dekking van de behoeftenIn verband met de lipiden (en in het bijzonder DHA), kan zich men de vraag stellen of de behoeften aan deze elementen gedekt zijn. Vele kinderen, en niet alleen prematuren, hebben een tekort aan DHA. Hoe kleiner ze zijn, hoe moeilijker ze het hebben om het te synthetiseren vanuit alfa-linoleenzuur. Suppletie van DHA is in deze gevallen nuttig om de behoeften te dekken.

De verschillende besproken thema’s doen besluiten dat de resultaten over de lipidensuppletie bij prematuren, die weinig overtuigend zijn in hun geheel, de noodzaak toonden om preciezere meetinstrumenten te gebruiken en homogenere groepen te bestuderen, om een groep van kinderen te definiëren die baat zal hebben bij deze suppletie van lipiden.

Malabsorption des lipides Dans tous les syndromes de malabsorption des lipides, il est très important de donner des suppléments, des vitamines,... Les études sur l’intérêt d’une supplémentation en lipides en cas de mucoviscidose sont peu nombreuses ; cependant en Scandinavie, le DHA est donné d’office par voie parentérale, aux enfants atteints de mucoviscidose lorsqu’ils sont hospitalisés, mesure fort couteuse. En cas de cholestase sévère, les enfants présentant des symptômes de déficit (atteintes cutanées très importantes) sont supplémentés en lipides, en plus d’une supplémentation en vitamines. Mais ceci ne s’applique qu’à des cas tout à fait particuliers. En effet, les cholestatiques sévères seront greffés à court terme et ceux qui présentent une cholestase modérée sont capables d’absorber une certaine quantité de lipides probablement souvent suffisante. Les enfants greffés ont un développement neurologique et ophtalmique qui parait correct. Il ne semble donc pas qu’il y ait e-u une carence irréversible ou de gros déficits en lipides, bien que l’atteinte soit très précoce, comme dans l’atrésie des voies biliaires par exemple. Alors qu’une supplémentation en protéines et en énergie peut avoir un rôle protecteur dans l’anoxie ischémique sévère rien de tel n’a été décrit pour les lipides.

Maladie péroxysmale La synthèse de DHA se passant dans les peroxysomes, les enfants souffrant d’une maladie peroxysomale ont souvent une carence en DHA. Certaines études, démontrent - mais pas toutes - un effet bénéfique sur la vision de suppléments en DHA chez ces enfants lorsqu’ils survivent plus longtemps.

Couverture des besoins A propos des lipides (et en particulier du DHA), on peut se poser la question de la couverture des besoins en ces éléments. De nombreux enfants, et pas uniquement les prématurés, présentent des carences en DHA. Plus ils sont petits, plus ils ont des difficultés à la synthétiser à partie de l’acide alpha-linolénique. L’apport en DHA est utile dans ces cas pour couvrir les besoins.

Les différents thèmes abordés amènent à conclure que les résultats sur la supplémentation en lipides chez les prématurés, peu convaincants dans leur ensemble, ont mis en évidence la nécessité d’utiliser des outils de mesure plus précis et d’étudier des groupes plus homogènes, afin de définir un groupe d’enfants qui tirera avantage de cet apport en lipides.

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DENOMINATION DU MEDICAMENT Enterol 250 mg, poudre pour suspension buvable. Enterol 250 mg, gélules. Saccharomyces boulardii. COMPOSITION QUALITATIVE ET QUANTITATIVE Enterol 250 mg, poudre pour suspension buvable : Chaque sachet-dose de poudre pour suspension buvable contient 250 mg de Saccharomyces boulardii sous forme lyophilisée (soit au minimum 6 x 109 cellules reviviscentes au moment de la fabrication et 1 x 109 cellules lyophilisées reviviscentes à la date de péremption). Enterol 250 mg, gélules : Chaque gélule contient 250 mg de Saccharomyces boulardii sous forme lyophi-lisée (soit au minimum 6 x 109 cellules reviviscentes au moment de la fabrication et 1 x 109 cellules lyophilisées reviviscentes à la date de péremption). FORME PHARMACEUTIQUE Enterol 250 mg, poudre pour suspension buvable : Poudre pour suspen-sion buvable. Enterol 250 mg, gélules : Gélule. Indi-cations thé-rapeutiques. Prévention de la diarrhée associée à l’antibiothé-rapie à large spectre chez des sujets prédisposés à développer une diarrhée à Clostridium dif� cile ou re-chute de diar-rhée à Clostri-dium dif� cile. Tr a i t e m e n t des diarrhées aiguës chez les enfants jusqu’à 12 ans, en com-plément de la réhydratation orale. Posolo-gie et mode d’administra-tion. Posolo-gie : Adulte : 2 à 4 gélules ou 2 à 4 sa-chets-doses par jour, en 2 prises. Enfant : 2 gé-lules ou 2 sa-chets-doses par jour, en 2 prises. Mode d’administra-tion : Gélules : avaler avec un peu d’eau. S a c h e t s -doses : diluer la poudre dans un verre d’eau. Durée du traite-ment : Pré-vention des récurrences ou rechute de diarrhée à Clostridium dif� cile : 4 se-maines. Traitement de la diarrhée en complément à la réhydratation orale chez l’enfant : 1 semaine. Contre-indications. Hypersensibilité à la substance active ou à l’un des excipients. Patients porteurs d’un cathéter veineux central. Aller-gie aux levures, spécialement Saccharomyces boulardii. Effets indésirables. Les effets indésirables sont classés ci-dessous par système-organe et par fré-quence comme dé� nies ci-après : très fréquents (≥ 1/10), fréquents (≥ 1/100, < 1/10), peu fréquents (≥ 1/1.000, < 1/100), rares (≥ 1/10.000, < 1/1.000), très rares (< 1/10.000), fréquence indéterminée (ne peut être estimée sur la base des données disponibles). Infections et infestations : Très rares : � èvre lors de fongémie à Saccharomyces boulardii, mycose à Saccharomyces boulardii.

Affections du système immuni-taire : Très rare : choc anaphylac-tique. Affections vasculaires : Très rare : choc anaphylactique. Affec-tions respiratoires, thoraciques et médiastinales : Très rare : dys-pnée. Affections de la peau et du tissu sous-cutané : Très rares : prurit, exanthème, Œdème de Quincke. Affec-tions gastro-intestinales : Très rares : constipation, épigastralgies, météorisme abdominal (épigastralgies et météorisme abdominal ont été observés lors d’études cliniques). Troubles généraux et anomalies au site d’administration :

Très rares : soif. Déclara-tion des effets indés i rab les suspectés. La déclaration des effets indé-sirables sus-pectés après autorisation du médicament est importante. Elle permet une surveil-lance continue du rapport b é n é f i c e /risque du mé-dicament. Les p r o f e s s i o n -nels de santé déclarent tout effet indési-rable suspecté via le système national de dé-claration. Bel-gique. Agence fédérale des médicaments et des produits de santé. Divi-sion Vigilance. EUROSTATION II - Place Vic-tor Horta, 40/ 40 - B-1060 Bruxelles - Site internet: www.afmps.be - e-mail: [email protected]. Luxem-bourg/Luxem-burg. Direction de la Santé – Division de la Pharmacie et des Médi-caments - Villa Louvigny – Allée Mar-coni - L-2120 Luxembourg

- Site internet : http://www.ms.public.lu/fr/activites/pharmacie-medicament/index.html. TITULAIRE DE L’AUTORISATION DE MISE SUR LE MARCHE BIOCO-DEX Benelux NV/SA - Square Marie Curie 20 - 1070 Bruxelles - BELGIQUE - Tél : 0032(0)23704790. NUMERO(S) D’AUTORISATION DE MISE SUR LE MARCHE Enterol 250 mg, poudre pour suspension buvable : BE 269026. Enterol 250 mg, gélules en � acon en verre : BE 269035. Enterol 250 mg, gélules en pla-quette: BE 397896. DATE DE PREMIERE AUTORISATION / DE RENOUVEL-LEMENT DE L’AUTORISATION Date de première autorisation : 22 novembre 2004. Date de dernier renouvellement : 23 avril 2010. DATE DE MISE A JOUR DU TEXTE Mise à jour : 02/2015. Approbation : 05/2015. MODE DE DELIVRANCE : Délivrance libre.

10 9,16 € 10 9,16 € 10 9,25 €

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Un bon réfl exe anti-diarrhée

Diarrhée aiguë* traitée

Équilibre intestinal restauré Patient rassuré

* chez les enfants jusqu’à 12 ans, en complément de la réhydratation orale

Enterol 2015_CampPro_Pédiatre_A4_5.indd 1 22/06/15 09:50


Neonatale enterovirusinfectie.

J.E. Deelen 1,2, S. Peeters ¹, Y. Vandenplas ²

¹ Dienst kindergeneeskunde, ASZ Aalst ² Dienst kindergeneeskunde, UZ Brussel.

[email protected]

Case Report

AbstractEnteroviral infections are common, especially in summer and autumn, and cause a broad spectrum of symptoms ranging from a slight increase in temperature and a common cold to potentially life-threatening multi-organ failure. The virus can be detected with RT-PCR in the stool, nasal secretions or in the cerebral spinal fluid. A curative treatment does not exist. In general, it is a self-limiting disease, but enteroviral encephalitis can induce white matter damage and neurological sequelae. Immunoglobulins may improve the outcome in case of severe enteroviral infections.

KeywordsEnterovirusinfectie, neonaten.

Binnen een periode van twee weken werd een drietal neonaten op onze afdeling kindergeneeskunde opgenomen met het klinisch beeld van een sepsis en meningitis. Twee van hen hadden meerdere dagen extra zuurstof nodig ter ondersteuning. Allen bleken besmet te zijn met een enterovirus. Een literatuurstudie werd uitgevoerd naar de achtergronden, klinische presentatie, behandeling en prognose van neonaten met enterovirus.

Casus 1Een a terme geboren meisje van vier dagen oud presenteert zich op de dienst spoedgevallen omwille van cyanose. Zij krijgt borstvoeding en bij het aanleggen aan de borst werd plots cyanose opgemerkt. Het meisje werd geboren na een probleemloze zwangerschap. De overige gezinsleden, ouders en een oudere zus, waren op het moment van presentatie geen van allen ziek. Bij klinisch onderzoek werd een roze, reactieve zuigeling gezien met een temperatuur van 36,7°C, een pols van 116 slagen per minuut en een goede saturatie (96%). Na korte tijd ontstond een apneu met cyanose en een desaturatie tot 44%, na stimulatie en het toedienen van extra zuurstof herstelde zij zich. Hart- en longauscultatie waren ongestoord en de fontanel was in niveau. Bij opname werd gestart met intraveneus antibiotica volgens neonataal sepsisprotocol. Bij toenemend geprikkeld zijn werd een lumbaalpunctie verricht. In de liquor werd met PCR een enterovirus gedetecteerd. Hemocultuur werd afgenomen en bleef negatief. Patiënte herstelde langzaam maar volledig.

Casus 2Een jongen van vier weken oud presenteert zich op de dienst spoedgevallen omwille van koorts. Sinds enkele uren heeft hij koorts tot 38,7°C en heeft moeder de indruk dat de ademhaling moeizaam gaat. Hij heeft iets minder gedronken dan normaal, is niet snotterig of aan het hoesten, heeft geen diarree en braakt niet. Bij klinisch onderzoek werd een zuigeling gezien met een volledig gemarmerde huid, een capillaire refill van 3 seconden, temperatuur van 38,2°C, pols van 177 slagen per minuut en een saturatie van 96%. Er is een wegdrukbare rash in het gelaat, de fontanel is in niveau, maar de jongen is erg geprikkeld bij onderzoek. Er is een normale hart- en longauscultatie. Een lumbaalpunctie werd verricht en een hemocultuur werd afgenomen. Bij opname werd gestart met intraveneus antibiotica volgens neonataal sepsisprotocol. De hemocultuur bleef negatief, maar in de liquor werd met PCR een enterovirus aangetoond. Patiënt herstelde probleemloos en binnen enkele dagen.

Casus 3Een jongen van twee weken oud presenteert zich op de consultatie kindergeneeskunde omwille van kreunen en koorts tot 38,6°C. Moeder had in de voorafgaande dagen een mastitis waarvoor zij behandeld werd met antibiotica. Bij klinisch onderzoek werd een kreunende zuigeling gezien met enige peribuccale cyanose en koude voeten. Zijn temperatuur bedroeg 38,1°C en hij had een pols van 170 slagen per minuut en een saturatie van 100%. Hart- en longauscultatie waren ongestoord en de fontanel was in niveau. Een hemocultuur werd

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Case Report

afgenomen en er werd gestart met intraveneus antibiotica volgens neonataal sepsisprotocol. Een dag na opname was hij toenemend geprikkeld en ontwikkelde hij saturatiedalingen waarvoor extra zuurstof nodig was. Na een lumbaalpunctie werd in de liquor met PCR een enterovirus gevonden. De hemocultuur toonde geen groei en de patiënt knapte goed op.

BesprekingEnterovirussen zijn enkelstrengs RNA-virussen die behoren tot de familie van de Picornaviridae. Deze omvat meer dan 100 serotypes, waarvan 10 tot 15 voornamelijk ziekteverschijnselen veroorzaken. De humane enterovirussen kunnen onderverdeeld worden in de poliovirussen en het humaan enterovirus type A tot en met D. 1, 2

Enterovirusinfecties komen verspreid over de hele wereld voor. In ons klimaat is er een piek in voorkomen in de zomer en de herfst. In landen met een tropisch of subtropisch klimaat kunnen ze echter het hele jaar door voorkomen. Bij neonaten is er geen duidelijke seizoensgebondenheid. Enterovirusinfecties komen frequent voor. Bij acuut ziek zijn met koorts is er in 33-65% van de gevallen sprake van een dergelijke infectie. Meer dan 25% van de symptomatische infecties komt voor bij kinderen jonger dan een jaar. Een aanzienlijk deel van de jonge kinderen die opgenomen worden met de klinische verdenking op een bacteriële sepsis blijkt uiteindelijk een enterovirusinfectie te hebben. 3, 4

Mensen zijn het enige bekende reservoir voor enterovirussen. De transmissie is voornamelijk feco-oraal of respiratoir. Neonaten kunnen reeds antenataal besmet raken, evenals intrapartum en direct postnataal. Verticale transmissie komt vooral voor als moeder besmet is geraakt met enterovirus tijdens het laatste trimester van de zwangerschap. Er zijn studies die beschrijven dat het virus aangetoond kan worden in het vruchtwater, de placenta en navelstrengbloed. Intrapartum kan een kind besmet raken door blootstelling aan maternaal bloed, genitale secreties en ontlasting. Postnatale besmetting verloopt via blootstelling aan orofaryngeale secreties van de moeder of andere individuen die in nauw contact staan met het kind. 3, 4, 5 Wanneer een moeder besmet is met een enterovirus, krijgt het kind via de placenta en eventueel later via de borstvoeding antilichamen. Aangezien er een grote diversiteit aan enterovirussen bestaat, is de passieve bescherming niet volledig. 6 Kinderen die volledig en exclusief borstvoeding krijgen gedurende de eerste levensmaanden, hebben een lager risico op infectie met een enterovirus. 7

De incubatieperiode van het virus is 3-6 dagen. Kinderen die geïnfecteerd zijn, zowel asymptomatisch als symptomatisch, blijven het virus nog geruime tijd uitscheiden. ³

Klinische presentatieEnterovirusinfecties kunnen een breed spectrum van symptomen veroorzaken. Deze kunnen variëren van zeer milde respiratoire verschijnselen tot potentieel levensbedreigend orgaanfalen. De meest voorkomende verschijnselen bij een neonatale enterovirusinfectie zijn koorts, prikkelbaarheid, lethargie en slecht drinken. Tot 50% van de zuigelingen ontwikkelt gedurende de ziekteperiode een maculeuze of maculopapuleuze rash. Respiratoire symptomen zoals neusloop, hoesten, kreunen en apneus worden eveneens bij ongeveer de helft van de kinderen gezien. Gastro-intestinale symptomen als diarree en braken komen minder vaak voor, maar toch nog in circa 20% van de gevallen. Enterovirussen veroorzaken vaak meningitis, vooral bij kinderen jonger dan drie maanden. Symptomen zijn prikkelbaarheid, slecht drinken en soms een bomberende fontanel. 4 Encefalitis is een zeldzame presentatie van een enterovirusinfectie. Een encefalitis veroorzaakt door enterovirus kan zich presenteren met veel verschillende symptomen of met een combinatie van symptomen: koorts, hoofdpijn, lethargie, sufheid, hepatosplenomegalie, afwijkende reflexen, convulsies en meningeale prikkeling zijn voorbeelden van symptomen. Nekstijfheid komt weinig voor, zeker bij kinderen jonger dan een jaar. ²In de minderheid van de gevallen ontstaat er een ernstig ziektebeeld met een combinatie van sepsis, meningoencefalitis, hepatitis, myocarditis en een coagulopathie. 3, 5

DiagnoseVan oudsher is de detectie van enterovirussen gebaseerd op isolatie van het virus in een celkweek. De sensitiviteit van deze methode ligt tussen de 50 en 75%. Nadeel van de methode is dat het erg lang duurt, namelijk 3-8 dagen. Met RT-PCR kan het proces flink versneld worden. Deze methode geeft in liquor en feces resultaten binnen 2-3 uur en heeft een sensitiviteit van 76-96% en een specificiteit van 96-100%. 2, 3, 4 Bepalen van het virus in serum is weinig sensitief en specifiek: in veel gevallen wordt het virus in serum niet aangetoond, terwijl het wel gevonden wordt in bijvoorbeeld feces of liquor. 8 Als er in het serum gezocht wordt naar enterovirus, moet dit gebeuren binnen 30 uur na het ontstaan van de symptomen en is het van belang dat het serum binnen 3 uur na afname wordt geanalyseerd. 9

BehandelingEr bestaat geen curatieve behandeling voor enterovirus. De infectie is over het algemeen self-limiting en vergt alleen ondersteunende behandeling. Bij neonaten zal doorgaans bij opname gestart worden met antibiotische behandeling, zeker als zij zich presenteren met het klinisch beeld van een sepsis of meningitis. Een prospectieve observationele cohortstudie uit 2011 laat zien dat het risico op een invasieve bacteriële infectie bij kinderen jonger dan 90 dagen met koorts en een bewezen enterovirusinfectie erg laag is, namelijk 1,6% (95% CI 0,04-8,4%) in vergelijking met 25,2% (95% CI 20,4-30,0%) bij kinderen jonger dan 90 dagen met koorts en bewezen negatief voor een enterovirusinfectie. 10 Wanneer bekend wordt dat er sprake is van een enterovirusinfectie en de hemocultuur is na 48 uur nog negatief, dan kunnen de antibiotica gestaakt worden.Toediening van immuunglobulinen is mogelijk zinvol in de zeer ernstige enterovirusinfecties met hepatitis, coagulopathie en/of myocarditis. Een recente retrospectieve studie toont dat het in een vroeg stadium, namelijk binnen 3 dagen na de start van de ziekte, toedienen van intraveneuze immuunglobulinen mogelijk een betere uitkomst geeft. 11

Complicaties en prognoseIn de meeste gevallen kent een enterovirusinfectie een ongecompliceerd klinisch beloop met volledig herstel en een goede prognose. De koorts verdwijnt gewoonlijk binnen 5 dagen, de overige symptomen verdwijnen doorgaans binnen een week. 4, 5

Risicofactoren voor ernstige ziekte zijn onder andere ziek worden in de eerste levensdagen, maternale ziekte kort voor de bevalling, prematuriteit, afwezigheid van neutraliserende antilichamen voor het specifieke type enterovirus en ernstige hepatitis en/of multi-orgaanfalen. 3, 4

Enterovirus myocarditis is zeldzaam maar kan ernstige gevolgen hebben. De mortaliteit ligt rond de 31%, en 66% van de overlevende kinderen heeft een ernstige hartaandoening, zoals chronisch hartfalen, aneurysmavorming in de linkerventrikel en mitralisklep regurgitatie. 12

Bij kinderen met een meningo-encefalitis door een enterovirusinfectie kunnen milde tot ernstige witte stofafwijkingen gevonden worden op echo cerebrum en MRI cerebrum. Afwijkingen in de witte stof kunnen aanleiding geven tot ontwikkelingsachterstand en in bepaalde gevallen tot cerebral palsy. 13, 14

BesluitEnterovirusinfecties zijn in 15-50% van de gevallen de oorzaak voor koorts bij neonaten. Ze komen relatief frequent voor en kunnen met name bij neonaten het klinische beeld veroorzaken van een sepsis of meningitis. Een curatieve behandeling is niet mogelijk en over het algemeen is de infectie self-limiting. Zeer ernstige infecties met hepatitis, myocarditis en coagulopathie kunnen echter voorkomen; in deze gevallen kan het vroegtijding toedienen van immunoglobulinen zinvol zijn. In deze groep van neonaten worden nog een aanzienlijke mortaliteit en restafwijkingen op lange termijn beschreven. De meeste patiënten met enterovirus zullen probleemloos genezen binnen een periode van ongeveer een week.


1. ICTV Virus Taxonomy, http://ictvonline.org/virusTaxonomy.asp?version=2012. Geraadpleegd 12-08-2015

2. Jain S, Bhupeswari P, Bhatt GC. Enteroviral encephalitis in children: clinical features, pathophysiology, and treatment advances. Pathog Glob Health 2014;5:216-222

3. Abzug, MJ. Nonpolio enteroviruses. In: Kliegman RM, Stanton BMD, St. Geme J, Schor N, Behrman RE, eds. Nelson textbook of pediatrics. 19th edition. Philadelpia: Elsevier Saunders; 2011:1088-1094

4. Tebruegge M, Curtis N. Enterovirus infections in neonates. Semin Fetal Neonatal Med 2009;14:222-227

5. Abzug MJ, Rotbart HA. Enterovirus infections of neonates and infants. Semin Pediatr Infect Dis 1999;10:169-176

6. Salur L, Oikarinen S, Tauriainen S, Mandel M, Hyöty H, Uibo R. Enterovirus infections in young infants. Are children still protected by maternal antibodies? Hum Vaccines 2011;7:9:966-971

7. Sadeharju K, Knip M, Virtanen SM, et al. Maternal antibodies in breast milk protect the child from enterovirus infections. Pediatrics 2007;119:941-946

8. Kupila L, Vuorinen T, Vainiopää R, Marila R, Kotilainen P. Diagnosis of enteroviral meningitis by use of polymerase chain reaction of cerebrospinal fluid, stool, and serum specimens. Clin Infect Dis 2005;40:982-987

9. Marque Juillet S, Lion M, Pilmis B,et al. Value of polymerase chain reaction in serum for diagnosis of enteroviral meninigitis. Arch Pediatr 2013;20:589-593

10. Martinez Planas A, Muñoz Almagro C, Luaces Cubells C, et al. Low prevalence of invasive bacterial infection in febrile infants under 3 months of age with enterovirus infection. Clin Microbiol Infect 2012;18:856-861

11. Yen MH, Huang YC, Chen MC, et al. Effect of intravenous immunoglobulin for neonates with severe enteroviral infections with emphasis on the timing of administration. J Clin Virol 2015;64:92-96

12. Freund MW, Kleinveld G, Krediet TG, Van Loon AM, Verboon-Maciolek MA. Prognosis for neonates with Enterovirus myocarditis. Arch Dis Child Fetal Neonatal Ed 2010;95:F206-212

13. Wu T, Fan XP, Wang WY, Yuan TM. Enterovirus infections are associated with white matter damage in neonates. J Paediatr Child Health 2014;50:817-822

14. Verboon-Maciolek MA, Groenendaal F, Cowan F, Govaert P, van Loon AM, de Vries LS. White matter damage in neonatal enterovirus meningoencephalitis. Neurology 2006;66:1267-1269

REFERENTIES :

Case Report

http://ictvonline.org/virusTaxonomy.asp?version=2012.

007;119:941-946


Crohn’s disease (CD) is increasingly diagnosed in the pediatric population. The incidence ranges from 2.5 to 11.4 per 100.000 in the North American and European Pediatric population, with 25-30% of all CD patients diagnosed before the age of 20years.1, 3, 5 Children often present with a more extensive disease and have a more complicated disease course. 5 This makes a more aggressive treatment often necessary, with frequent early initiation of immunomodulatory agents and biologicals. 5 Treatment goals in the pediatric population are not only the achievement of early mucosal healing, but also optimalisation of growth and development.

Infliximab (IFX) is a humanized chimeric monoclonal antibody against TNF-α, a pro-inflammatory cytokine playing a key role in autoimmune conditions, such as Inflammatory Bowel Disease (IBD). The early use of IFX, in combination with other immunomodulators, has been shown to induce remission more rapidly than the conventional ‘step-up’ treatment and decreases the need for treatment with corticosteroïds. 4 IFX is currently increasingly used for induction and maintenance therapy for CD in the pediatric population. 5

CaseWe present a case of Staphylococcus aureus discitis in a 16 year old girl treated with IFX. Our patient was diagnosed with extensive CD at the age of 12 years with involvement of the bulbus duodeni, terminal ileum, caecum and colon ascendens (Paris classification L4). Treatment with azathioprine and corticosteroids was

initiated. In the first months after diagnosis her disease was complicated with an abdominal abces, necessitating drainage, and development of stenosis of the terminal ileum, necessitating ileocaecal resection. Between the ages 13 to 16 years her disease was stable under treatment with azathioprine (dose of 50mg 1x/day). At 16 years of age she presented with vomiting and weight loss. Gastroscopy showed ulcerations with inflammatory stenosis of the pyloro-duodenal region. Biopsy showed signs of gastritis without the presence of H. Pylori. Treatment was altered to Modulen, omeprazole, Imuran (100mg 1x/day), methylprednisolone (2x20mg/dag during 1weak, followed by oral predisolon during 6 weeks) and Infliximab induction at week 0-2-6.

Gastro-intestinal symptoms subsided quickly, but complaints of lower back pain with limited lower back movements arised, subtle after the 2nd , but more pronounced after the 3rd dose of IFX. Biology showed inflammation (crp 92.8mg/l) and blood cultures were negative. Magnetic Resonance Imaging (MRI) and scintigraphy showed an L4-L5 discitis with destruction of the vertebral bodies, lower endplate L4 and upper endplate L5. Biopsy of the lumbar bone was performed and the culture was positive for Staphylococcus aureus. There was no evidence of direct external inoculation, such as adjacent wounds or skin infections, which suggested an haematogenous route of infection. Treatment with flucloxacilline for 6 weeks and corset for 3 months was provided. A good clinical evolution was seen with complete resolution of symptoms.

Staphylococcus Aureus discitis in a child with Crohn’s Disease treated with Infliximab: A case report.

K. Vergaelen ¹, B. Hauser ¹, D. Van Schaik ², A. Laumen ², E. De Greef ¹, T. Devreker ¹, G. Veereman ¹, J. Van der Werff ten Bosch ¹, Y. Vandenplas ¹

¹ Department of Paediatrics UZ Brussel. ² Department of Orthopedic Surgery UZ Brussel.

[email protected]

Case Report

Introduction

AbstractWe describe a case of Staphylococcus aureus discitis in a 16 year old girl treated with infliximab (IFX) for Crohn’s disease which is the first case described in the literature to the best of our knowledge. Tumor necrosis alpha (TNF-α) inhibitors, such as infliximab (IFX) are an effective therapy for moderate to severe inflammatory bowel disease (IBD), and are increasingly used in the adult and pediatric population. They are known to lead to an increased risk of opportunistic infections and the reactivation of latent Mycobacterium tuberculosis. We reviewed the association between anti- TNF-α therapy and the occurrence of serious infections in the pediatric population. The use of TNF- α inhibitors in children is associated with increased infections but the most frequently reported infections are mild and viral while severe bacterial and fungal infections are less common. Because of the rising incidence of pediatric IBD and increasing use of biological therapy, awareness of infections in this population is important for all care givers.



DiscussionThe use of infliximab in the pediatric population is often met with hesitation because of concerns about the increased risk of infections, particularly opportunistic infections, and malignancy. Patients are considered immunosuppressed if they receive corticosteroïd doses of ≥2mg/kg/day or ≥20mg/day, azathioprine dose of >3mg/kg/day or anti-TNFα therapy.

Studies in adults indicate that anti-TNFα therapy independently increases the risk of infections, in particular opportunistic infections. 4, 8, 9 This occurs at a higher incidence when concomitant immunosuppression is applied, particularly corticosteroïds. 4 The TREAT registry evaluated safety of IFX in adult patients and showed that a higher risk of serious infection was associated with disease severity at baseline (HR 2.24), the use of narcotic analgesics (HR 1.98), the use of prednisone (HR 1.57) and the use of IFX (HR 1.43). 4

A review of the literature concerning the pediatric population, showed a variable incidence of mild infections, ranging from 3% (1/38) to 77% (46/60) and an incidence of 0% (0-66) to 10% (6/60) for serious infections. 2 A broad spectrum of infectious agents was seen, such as disseminated varicella and CMV, listeria meningitis, histoplasmosis, pulmonary aspergillosis, non-tuberculous mycobacterial infection, bacterial sepsis and P. Jirovecii.

A meta-analysis of 65 pediatric studies performed in 2014 demonstrated that the rate of serious infections among children treated with anti-TNF-α agents (352/10.000 patient-years of follow-up (PYF)) was similar to the population treated with immunomodulator monotherapy (333/10.000 PYF), but significantly lower than the rate for pediatric patients treated with corticosteroïds (730/10.000 PYF) or adults treated with anti-TNFα agents (654/10.000 PYF). 3 The Reach study 7 demonstrated a higher efficacy of maintenance therapy with IFX when given every 8 weeks compared to every 12 weeks, but also a higher incidence of infections (73,6% vs. 38% in general and 8% vs. 5.7% for severe infections requiring hospitalization). 6, 7

However, large population-based cohort studies in the pediatric population are still lacking and the presence of an absolute increased risk of serious infection in children receiving anti-TNFα therapy still has to be confirmed.

This report describes a serious infectious complication in an adolescent with CD treated with infliximab. In contrast to the older population, discitis is an uncommon condition (0,3 per 100.000 persons) for persons under the age of 20 years. 10 Discitis refers to inflammation of the intervertebral disc, frequently with involvement of both adjacent vertebral end plates, suggesting significant overlap between discitis and vertebral osteomyelitis. Infection may be due to a wide range of organisms including Staphylococcus aureus (up to 50%), Coagulase-negative Staphylococci, gram negative bacteria (Kingella Kingae, E. coli, Pseudomonas,..), Streptococci and Tuberculosis.10 The most common mode

of infection is hematogenous spread, however inoculation from a diagnostic or surgical procedure or following a trauma may also occur. It’s diagnosis can be challenging since clinical features are often aspecific and fever may be absent. Examination of choice is MRI and CT guided biopsy, preferably before the initiation of antibiotic therapy. Scintigraphy can also localize the inflammation, but lack of specificity and imperfect sensitivity limits its utility. Empiric antibiotic therapy is not standardized but should include a combination of broad-spectrum antibiotics, directed against S. Aureus and gram negative bacteria, such as vancomycin – ceftriaxone. Later on it should be adjusted based on the microbiological results.

Early diagnosis and appropriate treatment of these infectious complications is important for a favorable outcome, but also prevention of these infections is important and possible on various levels, as described by the ESPGHAN IBD Porto Group in 2012. 6 A high level of suspicion for opportunistic infections is warranted, mandating a close follow-up and adequate patient education. Hygienic measures should be applied, including dietary precautions to avoid potentially contaminated foods and awareness concerning travelling. Disease related malnutrition is a frequent complication of IBD and associated with impaired immune function. 6, 8 Therefore nutritional status should be followed closely and corrected when needed. In severe forms of IBD with onset in early life, in particular under the age of five, underlying monogenic immunodeficiency’s should be suspected, necessitating a different therapeutic strategy. Screening for latent diseases such as tuberculosis should be done before initiating biologicals. Vigilance is recommended concerning immunizations and immunization schedule should be updated before starting immunosuppression, including Herpes Zoster vaccination unless there is a history of chickenpox or seropositivity. Yearly immunizations against influenza should be provided and live vaccines have to be avoided.

ConclusionsThe use of TNF-α inhibitors in children, in particular the combination with other immunosuppressive medications such as corticosteroïds, is associated with a higher risk of infections. Most frequent reported infections are mild and of viral origin, while severe bacterial and fungal infections are less common. Since the incidence of pediatric IBD and the use of biological therapy are rising, awareness of infections in this population is important for all care givers. Opportunistic infections pose a challenge for the clinician. They are often difficult to recognize and, without prompt diagnosis and subsequent therapy, are associated with important morbidity or mortality. Extra attention must also be paid to the prevention of these infection, as described by the ESPGHAN IBD Porto Group.

We describe an adolescent with CD who developed a Staphylococus aureus discitis of the lumbar vertebrae after the second dose of Infliximab, which is the first case described in the literature to the best of our knowledge. This case highlights the fact that clinicians should have a heightened awareness of the risk of opportunistic infections in patients with IBD treated with IFX or other biologicals.

Case Report


Figures 1: Endoscopy showing ulcerations with inflammatory stenosis of the pyloro-duodenal region

Figures 2: Scintigraphy and MRI: discitis L4-L5 with destruction vertebral bodies – lower endplate L4 – upper endplate L5

1. Borrelli O., Bascietto C., et al. Infliximab heals intestinal inflammatory lesions and restores growth in children with Crohn’s disease. Digestive and liver Dosease. 2004; 36: 342-347.

2. Toussi S., Pan N., et al. Infections in children and adolescents with juvenile idiopathic arthritis and inflammatory bowel disease treated with tumor necrosis factor-α inhibitors: Systematic review of the literature Clin Infect Dis. 2013; 57(9): 1318-1330.

3. Dulai PS., Thmpson K., et al. Risks of serious infection or lymphoma with anti-tumor necrosis factor therapy for pediatric inflammatory bowel disease: a systematic review. Clin Gastroenterol Hepatol. 2014; 12: 1443-1451.

4. Lichtenstein GR., Feagan BG., et al. Serious infection and mortality in patients with Crohn’s disease: More than 5 years of follow-up in the TREAt Registry. Am J Gastroenterol. 2012; 107(9):1409-1422.

5. Ruemmele FM., Veres G., et al. Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn’s disease. Journal of Crohn’s and Colitis. 2014; 8: 1179-1207.

6. Veereman-Wauters G., de Ridder L., et al. Risk of infection and prevention n Pediatric Patients with IBD: ESPGHAN IBD Porto Group Commentary. JPGN. 2012; 54:830-837.

REFERENCES :

7. Hyams J., Crandall W, et al. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology 2007; 132: 863-73.

8. Hartman D., Eliakim R., et al. Nutritional status and nutritional therapy in inflammatory bowel diseases. World J Gastroenterol 2009; 15: 2570-8.

9. Ardura M., Toussi S., et al. NASPGHAN Clinical report: Surveillance, Diagnosis and Prevention of Infectious Diseases in pediatric patients with inflammatory bowel disease receiving Tumor necrosis factor-α Inhibitors. JPGN

10. Fernandez M,, Carrol CL,, et al. Discitis and vertebral osteomyelitis in children: an 18-year review. Pediatrics 2000; 105:1299.

11. Nigrovic, P.A.Author. (2015). Back pain in children and adolesents: Overview of causes. Retrieved from http://www.uptodate.com

Case Report

http://www.uptodate.com/


Polyethylene glycol (PEG) electrolyte solution was developed in 1980 as an osmotic laxative by Davis et al ¹. It is commonly used for bowel preparation before colonoscopy in both adults and children because it is both effective and well tolerated. As PEG needs to be ingested in large volumes to be effective ², it is frequently administered via a nasogastric (NG) tube. Common adverse effects of PEG include nausea, vomiting, abdominal fullness and bloating. Serious adverse effects are rare and include angioedema, anaphylaxis, electrolyte disturbance with risk of cardiac arrhythmia and pancreatitis ³. The osmotic properties of PEG can be hazardous when it is administered outside of the gastro-intestinal tract. When it is aspirated into the lungs it can cause significant inflammation resulting in pulmonary edema, which can be life-threatening and even fatal 4-8. In this report, we present a patient who develops acute respiratory distress syndrome after aspiration of PEG but was successfully treated with bronchoalveolar lavage (BAL).

Case reportA 16 year old boy with Crohn’s disease was admitted to the hospital for intestinal lavage with polyethylene glycol solution via NG tube prior to a gastro- and colonoscopy. The NG tube placement was performed by the ward nurse according to our routine protocol with placement verification by means of auscultation of air insufflation over the abdomen. Yet the initiation of PEG infusion resulted in coughing and frequent swallowing. One hour later he developed respiratory

distress and his oxygen saturation decreased to 85% in room air. Physical examination revealed bilateral crackles and progressive respiratory distress. Because pulmonary aspiration of PEG was suspected, the PEG infusion was halted and the NG tube removed. The patient was placed on supplemented oxygen therapy via a non-rebreathing mask (10 l/O2/min). Oxygen saturation subsequently increased to 95%. A chest X-ray (panel A) revealed bilateral infrahilar pulmonary infiltrates. A venous blood gas analysis was obtained while the patient was on 100% oxygen supplement and showed a pH of 7.32, a pCO2 of 49.4 mm Hg, a pO2 of 34 mmHg with a -0.7 base excess and a bicarbonate of 25 mmol/L. He was immediately started on intravenous methylprednisolone (at a dose of 2mg/kg/day) and amoxicillin-clavulanic acid (at a dose of 100mg/kg/day). A bronchoscopy under general anesthesia was performed 3 hours after the incident and extensive bilateral broncho-alveolar lavages were conducted to remove as much aspirated PEG solution as possible. During bronchoscopy a diffuse inflammation of the airways was seen. A large amount of pink-yellowish fluid was aspirated mainly from the left lung. BAL volumes were not noted. The patient was extubated immediately after the procedure and admitted to the intensive care unit for observation. Oxygen therapy was continued for 3 days until the spontaneous resolution of his symptoms. The chest X-ray on discharge 9 days later revealed a near complete resolution of the infiltrates and some residual hyperinflation (panel B). Lung function was not performed at convalescence.

Acute respiratory distress during colonoscopy preparation: case report and brief overview of literature.

G. VAN MOER ¹, I. HOFFMAN 1,2, M. PROESMANS 1,2, J. TOELEN 1, 2

¹ Department of Pediatrics, UZ Leuven. ² Department of Development and Regeneration, Group of Biomedical Sciences, KU Leuven.

[email protected]

Case Report

Introduction



Case Report

DiscussionThere are only a limited number of case reports in both pediatric and adult literature that describe respiratory failure after aspiration of PEG (see table). The patient in our case developed symptoms rapidly after starting the PEG infusion via nasogastric tube. Our hypothesis is that the NG tube was either accidently placed in the oesophagus or trachea or migrated into the trachea during the coughing and swallowing. The infusion of PEG at a rate of 250 ml/hr in a tube with a esophageal position may have led to stasis of fluid in the oesophagus and subsequent aspiration into the trachea. It would also be possible that the tube was inadvertently placed in the trachea as the respiratory symptoms began nearly immediately after starting the infusion. It has been shown that malposition of a NG tube occurs in less than 1/1000 cases of patients with a normal mental status 9. As soon as the respiratory distress was diagnosed, the PEG infusion was stopped and the NG tube removed. The patient was started on IV antibiotics and steroids to prevent aspiration-induced-pneumonia (possible bacterial contamination of fluid from inside the esophagus) or pulmonary chemical inflammation (due to the macrogol). Several case reports have advocated the use of BAL to prevent pulmonary damage thus shortening the need for ventilatory support and hospitalization 12, 13. There is evidence from animal studies that PEG infusion into the lung induces lung edema and ARDS 14. On the other hand Gursahani et al. showed that PEG polymers can be absorbed across epithelial membranes in the rodent lung (with an estimated half-life of 9-10 hours) 15. We decided to perform an early bronchoscopy with lavages to prevent extensive pulmonary edema and progression to respiratory failure. This decision was mainly based

on the available reports in literature and the pathophysiological reasoning. We are aware that there may be a publication bias towards cases with this type of intervention, which may influence the clinical decision making. We only found one single report of a case of PEG aspiration that was treated successfully with conservative management 16. It is possible that our patient’s clinical condition would have improved after spontaneous resorption of the aspirated PEG yet the reduction in the oxygen administration immediately after the BAL suggests at least some clinical effect of the intervention. On the other hand bronchoscopy remains an invasive procedure that requires sedation or general anesthesia and may thus not be imperative in patients with only a moderate respiratory distress. When reviewing this case at a multidisciplinary team meeting, the question was posed if this type of complication could have been prevented with a different NG tube position verification. Next to the auscultatory method, the only other option is a chest X-ray. Yet the rarity of this complication does not outweigh the radiation exposure by routine X-ray testing of these patients. We suggest that careful verification of the position of the NG tube is always needed before starting PEG at a low infusion rate and vital signs should be checked regularly during administration. A correct position of the NG tube would ideally be confirmed with chest X-ray in the event of heavy coughing, swallowing or difficult placement.

Conflict of InterestThe authors declare that there is no conflict of interest regarding the publication of this paper.


Case Report

Table: Case reports describing respiratory failure after PEG aspiration

Age (yr) Context Symptoms Therapy Outcome Reference

5 ConstipationStupor, tachypnea, cyanose

Mechanical ventilation Not stated [6]

7 ConstipationCoughing, vomiting, respiratory failure

IV steroids, DiureticsIV antibioticsMechanical ventilation

Recovery [11]

8 ConstipationAbdominal discomfort, gagging, vomiting, coughing, ARDS

Mechanical ventilation Recovery [10]

8 ConstipationVomiting, tachypnea, chest pain

Diuretics, IV steroids IV antibiotics, BALMechanical ventilation

Recovery [12]

9Bowel preparation before surgery

Coughing,gagging, vomiting, tachypnea

IV steroidsIV antibioticsSupplemental oxygen

Recovery [16]

11 Constipation Respiratory failure Mechanical ventilation Not stated [4]

59 Exclude malignancy Vomiting, aspirationIV steroids, DiureticsIV Ofloxacin

Recovery [8]

60 Exclude malignancy Respiratory failure Mechanical ventilation Death [7]

70 Abdominal painVomiting, dyspnea, ARDS

Mechanical ventilationBAL, IV steroidsIV antibiotics

Recovery [13]

78Pre-operative bowel surgery

Vomiting, dyspnea, ARDS

DiureticsMechanical ventilation

Death [8]

80 Exclude malignancyVomitingRespiratory failure

BALMechanical ventilation

Recovery [8]

86 Exclude malignancyNausea, vomitingRespiratory failure

IV antibioticsMechanical ventilationBAL

Death [5]

1. Davis GR, Santa Ana CA, Morawski SG, Fordtran JS. Development of a lavage solution associated with minimal water and electrolyte absorption or secretion. Gastroenterology 1980; 78: 991–5.

2. Dahshan A, Lin CH, Peters J, Thomas R, and Tolia V. A randomized, prospective study to evaluate the efficacy and acceptance of three bowel preparations for colonoscopy in children. The American Journal of Gastroenterology, vol. 94, no. 12, pp. 3497–3501, 1999.

3. Belsey J, Epstein O, and Heresbach D. Systematic review: adverse event reports for oral sodium phosphate and polyethylene glycol. Alimentary Pharmacology andTherapeutics, vol. 29, no. 1, pp. 15–28, 2009.

4. Narsinghani U, Chadha M, Farrar HC, Anand KS. Life threatening respiratory failure following accidental infusion of polyethylene glycol electrolyte solution into the lung. J. Toxicol. Clin. Toxicol. 2001; 39: 105–7.

5. de Graaf P, Slagt C, de Graaf JL, Loffeld RJ. Fatal aspiration of polyethylene glycol solution. Neth J Med. 2006 Jun; 64(6): 196-8.

6. Argent A, Hatherill M, Reynolds L, Purves L. Fulminant pulmonary oedema after administration of a balanced electrolyte polyethylene glycol solution. Arch Dis Child. 2002 Mar;86(3):209.

7. Hasan AG, Brown WR. Colonic cleansing for colonoscopy: a risk to be taken seriously. Gastrointest Endosc. 2011 Mar;73(3):616-8.

8. Marschall HU, Bartels F. Life-threatening complications of nasogastric administration of polyethylene glycol-electrolyte solutions (Golytely) for bowel cleansing. Gastrointest Endosc. 1998 May;47(5):408-10.

9. Sorokin R, Gottlieb JE. Enhancing patient safety during feeding-tube insertion: a review of more than 2,000 insertions. J Parenter Enteral Nutr. 2006 Sep-Oct; 30(5): 440-5.

10. Paap CM, Ehrlich R. Acute pulmonary edema after polyethylene glycol intestinal lavage in a child. Ann Pharmacother. 1993 Sep;27(9):1044-7.

REFERENCES :

11. Wong A, Briars GL. Acute pulmonary oedema complicating polyethylene glycol intestinal lavage. Arch Dis Child. 2002 Dec;87(6):537

12. Liangthanasarn P, Nemet D, Sufi R, Nussbaum E. Therapy for pulmonary aspiration of a polyethylene glycol solution. J. Pediatr. Gastroenterol. Nutr. 2003; 37: 192–4.

13. Hur GY, Lee SY, Shim JJ, In KH, KangvKH, and Yoo SH. Aspiration pneumonia due to polyethylene glycol-electrolyte solution (Golytely) treated by bronchoalveolar lavage. Respirology. 2008 Jan;13(1):152-4.

14. Güzel A, Güzel A, Günaydin M, Alaçam H, Saliş O, Sükrü Paksu M et al. The role of iNOS inhibitors on lung injury induced by gastrointestinal decontamination agents aspiration. J Mol Histol. 2012 Jun;43(3):351-60.

15. Gursahani H, Riggs-Sauthier J, Pfeiffer J, Lechuga-Ballesteros D and Fishburn CS. Absorption of polyethylene glycol (PEG) polymers: the effect of PEG size on permeability. J Pharm Sci. 2009 Aug;98(8):2847-56.

16. Mosquera RA, McDonald M and Samuels C. Aspiration pneumonitis caused by polyethylene glycol-electrolyte solution treated with conservative management. Case Rep Pediatr. 2014 May;2014:872634.


The renewed interest for defects in the innate immune system found its origin in the observation that even in the 21st century despite asepsis, despite improved hygiene measures, despite the improved general health status, despite the availability of vaccines, antibiotics, antifungal and antiviral agents, each year, children without known chronic conditions still die of infection with pathogens that only cause mild illness in most children. In fact, this extreme variability in the susceptibility to and severity of infectious disease with a particular pathogen has been puzzling scientists and physicians for decades. Several theories have been set forward to explain this variability. The microbiological or germ theory is apt to explain this difference at the level of the germ. However, even during epidemics it became clear that there was interindividual variability showing that microbes are essential yet not sufficient to develop disease from infection. Ee.g. less than 10% of individuals infected with Mycobacterium tuberculosis go on to develop tuberculosis. Even the virulence of a certain virus cannot explain the inter-individual differences observed during a given epidemic in the same area. With the birth of immunology, this inter-individual variation was explained by the concept of humoral and cellular immune responses to a previous encounter with the same microbe or with a related microbe. However, this immunological theory can only be brought up at the level of secondary infection in older individuals. It cannot explain the clinical heterogeneity in the course of primary infection with a new pathogen, which is typically the case for young children. Surprisingly the hint to the answer came from both plant and mouse geneticists with Mendel showing genetic differences underlying vulnerability or resistance of wheat to “yellow rust” and with the genetic unraveling in mice of syndromic asplenia and susceptibility to influenza. These and other studies provided a strong molecular basis for the Mendelian inheritance of resistance or susceptibility to a specific infectious agent. It took the advent of antibiotics for the first primary immunodeficiency (PID) to be described in humans. Indeed, the first X-linked agammaglobulinemia patient described by Ogden Bruton, had suffered from numerous episodes of pneumococcal meningitis, each time cured by antibiotics. Without this treatment, the patient would not have been discriminated from many others dying from the “collective“ burden of infections. At that time, thanks to the advances in immunology, the medical community had access to measuring techniques (e.g. antibody determination by eletrophoresis). Unfortunately this advantage paradoxically hindered the development of the field of PID as it was believed that patients with PID were

exceptional cases suffering from recurrent severe infections with a multitude of so-called opportunistic pathogens in a fully penetrant manner with an early onset and with measurable anomalies in the immune system narrowed down to the hematopoietic system. Up till now, it is hard to convince anyone that a fatal or near fatal-infection with a common germ like influenza or measles may be due to immunodeficiency even in the absence of measurable defects and case reports entitled “Fatal invasive candididasis in an immunocompetent child” are still being published. Nevertheless, the genetic theory of infectious diseases gained field. In this theory it is hypothesized that life-threatening disease in the course of primary infections results from single-gene inborn errors of immunity, displaying low, intermediate or high but rarely complete penetrance. It is especially in the context of this paradigm that errors in the innate immune system have been described.

Defects in the innate immune system

The natural or innate immune system is the part of the immune system that is capable of protecting the host against microbial invasions without the need for prior exposure. The innate immune system was the first to develop phylogenetically. Moreover, the innate immune system does not display memory responses upon a second exposure to a given pathogen. Against the disadvantage of lack of amplified response, stands the advantage of the nonspecific response to protect against multiple diverse pathogens. Unlike the adaptive immune system responses, innate immune responses are immediate responses, within minutes to hours after invasion. As a result, defects in the innate immune system ensue rapidly in infection. Most components are mature at birth, which is another advantage. Finally, cells and responses of the innate immune system work to augment the function of the adaptive immune system. For instance: after opsonisation of a microbe by antibodies (humoral arm of the adaptive immune system), cells of the innate immune system will eliminate the microbes.

The innate immune system is a diverse system first composed of mechanical barriers prohibiting the entry or organisms: epithelia, mucosal membranes and the mucins and cilia linked thereto. Second a variety of cells is involved and exerts several functions ranging from antigen presentation (dendritic cells) to direct cytotoxic effects (natural killer cells, neutrophils producing reactive oxygen and nitrogen species) and phagocytosis. Third a set of proteins together

Inborn errors of immunity: the natural or innate immune system and phagocyte defects.

Isabelle Meyts

UZ Leuven, Department of Pediatrics, Primary Immunodeficiencies.

[email protected]

State of the Art



Figure 1. Algorithm for the differential diagnosis of defects in the innate immune system.

State of the Art

acting as the complement system should not be underestimated. Defects in the complement system are the subject of another section. In brief, defects in the early components can result in a combinataion of pyogenic infection with auto-immune disease, whereas defects in C3 and regulatory proteins result in invasive infection with encapsulated organisms and whereas defects in the late components of the complement system result in recurrent invasive infection with Neisseria meningitides. Fourth, there is a set of microbial receptors that act on the surface of most cells of the natural immune system, to recognize specific patterns associated with groups of microbes e.g. the Toll-like receptors recognizing single

stranded or double stranded DNA or RNA etc. This paradigm of pattern recognition results in specific disease phenotypes with defects in the TIR pathways resulting in susceptibility to infection with a limited number of pathogens. This partially translates in defects of the innate immune system leading to susceptibility to infection with a limited number of pathogens. Within the errors of the innate immune system, several phenotypic presentations stand out: presentation with 1/ invasive pyogenic infections 2/ severe viral infection 3/ fungal and parasitic infection 4/ mycobacterial infection. (Figure 1).

Defects in innate immunity

Predominant susceptibility to invasive infections with pyogenic

bacteria

Predisposition toinvasive bacterialinfections (meningitis, sepsis, arthritis, osteomyelitis andabscesses), often in theabsence of fever.

Predominant pathogens(S.pneumoniae, S. Aureus and Pseudomonas aeruginosa). Non-invasivebacterial infections (skin infections and upperrespiratory tractinfections). Improve withage.

Routine screening tests are normal. Specificscreening tests (lack of proinflammatory cytokine productions and CD62L shedding): available onlyin specialized clinicalimmunology laboratories.

IRAK4 def (IRAK4)

MyD88 def (MYD88)

Bacteremia(encapsulated bacteria) no spleen

Isolated

Congenital

Asplenia

(RPSA)

Predominant susceptibility to viral infection Parasitic infections andfungal diseases

Susceptibility toMycobacteria

Herpes simplex Encephalitis

Dominant clinicalphenotype is herpes simplex encephalitis (HSE) during primary infectionwith herpes simplex virus type 1 (HSV1), usuallybetween 3 m onths and 6 years of age.

Routine screening tests are normal.

Specific tests examiningthe TLR3 pathway: markeddecrease in the ability of patient’s fibroblasts toproduce IFN-β/-λ in response to TLR3 agonistsand HSV1 infection.

AR : UNC9381TLR3 TRIF

AD: TLR3TRIFTRAF3TBK1

Warts, Hypogammaglobulinemia, infectons, Myelokathexis

AD. Neutropenia, reducedB cell numbers.Warts/human papillomavirus infectionWHIM sd (CXCR4)

Human papilloma virus (group B1) infections andskin cancerEpidermo-dysplasiaverruciformis(EVER1/TMC6, EVER2/TMC8)

Viral infectionsSTAT1 defSTAT2 deficiency

Severe viral infectionsCD16 def

Severe influenza diseaseIRF7 def

CMC

ChronicmucocutaneousCandidiasis

OccasionallyAutoimmunity,No ectodermaldysplasia

AD: STAT1 (gain of function) IL17F

AR: IL17RAIL17RC

Invasive cadidiasisor dermatophyticDiseaseCARD9 def(CARD9)

Blepharitis, Folliculitis andMacroglossiaACT1 def (ACT1)

Susceptibility toMycobacteria, Candida, Myeoloproliferation

IRF8 def (AR form) (IRF8)

Susceptibility toMycobacteria, Candida, RORc def (RORC)

MSMDIL12 –IFNγ axis def.

AD IFNGR1 (mycobacterialosteomyelitis).

Complete AR IFNGR1 andAR IFNGR2 (seriusdisseminated BCG andenvironmentalmycobacteria infections(soft tissue, bone marrow, lungs, skin, bones andlymph nodes), Salmonellaspp., Listeria Monocytogenes and viruses

Parital STAT1 LOF (AD), Partial IFNγR1, partialIFNγR2, complete IL-12Rβ1, complete IL-12B, complete ISG15, XL CYBB, IRF8, Tyk2, XL NEMOusually less severe

1. Patients presenting with invasive pyogenic infection: think of defects in the Toll/Interleukin-1R (TIR) pathway.

Who is suspect of having a disturbance in the TIR pathway? Children with recurrent invasive pneumococcal and/or staphylococcal disease, recurrent non-invasive pyogenic infections (e.g. cellulitis), severe fungal infections or recurrent mycobacterial disease should be tested for defects in the TIR pathway. Indeed children suffering from deficiency in IRAK4, MyD88, NEMO, and IKBA are prone to life-threatening with Streptococcus pneumonia, Staphylococcus aureus and Pseudomonas aeruginosa. Typically the work-up of any child presenting with (recurrent) invasive pyogenic infection should include: 1) full blood count with white blood cell differential to rule out neutropenia (esp. in the context of the recurrent cellulitis component)

2) functional complement assays via both alternative and classical pathway (AP50 and CH50) and combined with individual component analysis if in doubt. Recurrent Neisseria meningitides infection in particular suggests a defect in the terminal complement cascade.

2) confirmation of the presence of a functional spleen (ultrasound, Howel-Jolly bodies). Isolated congenital asplenia is a rare condition resulting from RPSA haploinsufficiency, however secondary asplenia or functional asplenia is much more common.

3) measurement of antibody levels (IgG, IgA, IgM) and anticapsular polysaccharide

IgG production after vaccination with Pneumo23® as a measure of are another important warning sign that should lead to further evaluation (see Table 1).

4) in vitro TIR pathway analysis – in some cases the pathway needs to be analysed on fibroblasts (e.g. TLR3 deficiency) because the phenotype is not apparent in blood cells.

In addition the presence of ectodermal dysplasia +/- anhydrosis and colitis should alert the clinician to think about NEMO deficiency. Patients (mostly children and infants) with autosomal recessive (AR) IRAK-4- or MyD88-deficiency have apparently normal T- and B-cell responses but suffer from recurrent pyogenic bacterial infections. These infections can be invasive (e.g. meningitis, sepsis, arthritis, osteomyelitis, and abscesses) or noninvasive (e.g. skin and upper respiratory tract infections) and are mostly caused by Streptococcus pneumoniae, Staphylococcus aureus or Pseudomonas aeruginosa. Delayed separation of the umbilical cord and pyogenic omphalitis is another important sign. The polysaccharide-specific antibody response is impaired in some patients and, because of inhibition of NF-κB signaling, they have a mild early inflammatory reaction in terms of fever and in terms of neutrophil counts. Prophylaxis with antibiotics and vaccines is therefore an important measure to counter these life-threatening infections. The phenotype improves with age, but even in adulthood, patients continue to suffer from noninvasive bacterial infections of the skin and upper respiratory tract.


State of the Art

Some defects downstream in the TIR pathway result in a more severe phenotype, and render patients susceptible to infection with a myriad of pathogens.Hypermorphic mutations of the autosomal NFKBIA gene and hypomorphic mutations of the X-linked IKBKG gene cause autosomal dominant (AD) and X-linked recessive anhidrotic ectodermal dysplasia (EDA) with immunodeficiency (EDA-ID) syndromes, respectively. Both these defects can impair NF-κB-mediated cellular responses to multiple receptors, including members of the TLR, IL-1R, TNF-R, TCR, and BCR families. As a result of this broader cellular response, these patients suffer from infections caused not only by (pyogenic) bacteria, but also by mycobacteria, fungi or viruses. Most patients with EDA-ID do not generate polysaccharide-specific serum antibodies and have a mild inflammatory reaction. Impaired signaling through the ectodysplasin receptor (EDA-R) signaling pathway explains why patients also have EDA, with sparse hair, abnormal teeth (tooth agenesis, conical teeth) and hypohydrosis. Prophylaxis is a key element of treatment. Antibiotics and vaccines should be supplemented with intravenous or subcutaneous IgG substitution, depending on the nature of B-cell immunity impairment. In severe deficiencies, hematopoietic stem cell transplantation should also be considered. Likewise, homozygous IKKβ (IKBKB gene) mutations lead to a severe combined immunodeficiency (SCID) phenotype despite the presence of a normal number of B- and T-cells. Patients present with failure to thrive and life-threatening viral, bacterial, and fungal infections. Other defects related to the TIR pathway have been described and usually result in a combined immunodeficiency phenotype with hypogammaglobulinemia and opportunistic infections (mutations in CARD11, BCL10, and MALT1).

2. Patients suffering from severe viral infection.

Children with isolated HSV1 encephalitis (or by extrapolation other herpesviruses) should be investigated for defects in the TRIF pathway both on blood as well as on skin-derived fibroblasts. Herpes simplex virus type 1 encephalitis (HSE) should always alert the clinician to an underlying inborn error of immunity. Defects in the TRIF-dependent pathway (AR/AD TLR3, AR UNC-93B, AR/AD TRIF, AD TRAF3, AD TBK1, or AD IRF3 deficiencies) have been described in these patients. TLR3 is widely expressed in the central nervous system (CNS), lymphocytes, epithelial and dendritic cells. It is vital for protective immunity against herpes simplex virus 1 (HSV-1) in the CNS during primary infection in childhood, but seems to be redundant for host defense against HSV-1 and most microbes in other tissues. HSE pathogenesis is caused by low levels of type I interferon production by CNS-resident cells in response to primary HSV-1 infection. This was demonstrated through the use of iPSC-derived CNS-resident cells, including neurons, oligodendrocytes, and astrocytes. Patients with these deficiencies may therefore benefit from recombinant interferon-α treatment, as suggested on the basis of studies of mouse models of HSE.

What holds true for HSV-1, holds true for any other virus: in a child presenting with a severe viral infection (at the extremes of the Gauss curve), screening of the immune system is necessary. If this child was previously perfectly healthy, then a defect in the innate immune system is more likely. For instance, severe influenza related necrotizing pneumonia was found to be associated with IRF7 deficiency. Another examples is STAT2 deficiency, which results in defective signal transduction downstream from the IFN-alpha receptor, there is no upregulation of IFN-alpha induced genes, which is crucial for defense against

many viral infections. In particular, in the kindreds described until now, severe complications following immunization with live measles-mumps-rubella vaccine seems to stand out as the most penetrant phenotype. It may be clear that the latter deficiencies are not easily found from routine blood analysis but require next generation sequencing or panel sequencing as there will be no anomalies on routine analysis of blood samples. Complete STAT1 deficiency is another example where defects in the signaling cascade downstream from interferon results in fatal viral infections next to increased susceptibility to infection with mycobacteria.

3. Chronic mucocutaneous candidiasis

Severe candida infection can be a feature of many primary immunodeficiency syndromes. Severe and persistent trush and Candida diaper dermatitis and Candida oesophagitis in an infant should always alert to the diagnosis of Severe Combined Immune Deficiency. Mucocutaneous candidiasis can also be a feature of syndromic immunodeficiency: e.g. the Automosal Dominant Hyper-IgE syndrome due to dominant negative loss-of-function mutations in STAT3 or due to mutations in AIRE, leading to Autoimmune-Polyendocrinopathy-Enteropathy-Candidiasis-Ectodermal Dystrophy syndrome. Chronic mucocutaneous candidiasis (CMC) refers to the chronic infection of skin, nails and mucosa with Candida species as a more or less isolated syndrome. Central in this presentation is a lack of sufficient Th17 responses. Th17 cells represent a subset of helper T cells, producing the cytokine IL-17. Probably over 50% of CMC patients have a gain-of-function mutation (GOF) in STAT1. The mutations typically also lead to excessive IFN-alpha signalling which explains why there are also auto-immune and lupus-like phenomena associated to this condition, with auto-immune thyroiditis related hypothyroidism being the most common problem. A typical presentation of this patient could be recurrent candida oesophagitis, aphtous stomatitis, onychomycosis. Some patients also have celiac like bowel disease. Recently there has also been reports on patients with STAT1 GOF mutations presenting with a SCID phenotype.Mutations in many more genes related to the Th17 pathway have been shown to be causative of CMC in these patients, the latest being RORGT deficiency. RORGT is a central transcription factor needed for Th17 cell development. Autosomal recessive defects in CARD9 lead to susceptibility to severe fungal infections, e.g. mucocutaneous candidiasis, Candida sp. CNS-infections, deep dermatophytosis, and subcutaneous phaeohyphomycosis. CARD9 is important for NF-κB activation through Dectin-1, a C-type lectin receptor that senses fungal infections through β-glucan recognition. Impairment of this signaling cascade leads to a significant decrease in Th17 cells.

4. Mendelian Susceptibility to Mycobacterial Disease (MSMD)

MSMS is a condition characterized by recurrent and severe infection with environmental mycobacteria but also with Mycobacterium tuberculosis. The defects typically are related to the IL-12/interferon-gamma pathway. IL-12 stimulates via the IL-12 receptor and JAK2 the secretion of IFN-gamma. IFN-gamma is essential in rendering macrophages capable of confining (in granuloma formation) and killing mycobacteria. Many gene defects have been described in this pathway as exemplified in the algorithm. Some are associated with other infections like Salmonella sp. or severe (life-threatening) viral infection.


State of the Art

Phagocyte defectsPhagocytes are an important component of the innate immune system. However phagocyte defects rerpresent a separate group of disorders. The defect can be either quantitative (neutropenia) or qualitative. (Figure 2).

1. Neutropenia

Central in the work-up of any patient with neutropenia is repeated blood sampling (ideally 2x per week during 6 weeks) with white blood cell differentials. Anti-granulocyte antibodie measurement is also crucial, even if the test is not very sensitive.Severe congenital neutropenia is a rare disorder characterized at the clinical level by life-threatening pyogenic infections from birth (e.g. omphalitis, cutaneous abscesses, oral ulcres, pneumonia and otitis media). A stop in the myeloid differentiation upon bone marrow exam is diagnostic. This condition was invariably fatal prior to the introduction of G-CSF therapy in the 80’s. In cases unresponsive to G-CSF and even in all other cases HSCT is an option esp. since severe congenital neutropenia is associated with increased risk of leukemia. Several gene defects have been described such as mutations in HAX1, ELANE, Gfi1, JAGN1. Specific mutations in ELANE result in cyclic neutropenia in which there are oscillations in the production of all types of blood cells with symptoms deriving mostly from the neutropenia.

2. Chronic granulomatous disease (CGD)

CGD is a heterogeneous group of inborn disorders of phagocyte function due to defects in the NADPH enzyme complex. Patients with CGD suffer from recurrent life-threatening infection with bacteria and fungi. Moreover they have an excessive inflammatory response characterized by granuloma formation. The granuloma formation can be the first sign of the disease in the form of inflammatory bowel disease, reminiscent of Crohn’s disease. Some cases

are misdiagnosed as sarcoidosis, inflammatory bowel disease, eosinophilic pneumonitis / oesophagitis or even hyper-eosinophilic syndrome. Mutations affecting the distinct subcomponents of the NADPH complex are causative of the disease. The most common form is the X-linked form is caused by mutations in gp91phox and accounts for up to 70% of cases.

CGD can present from infancy to adulthood but most cases are diagnosed in early childhood. Typical infections are pneumonia, abscess, lymphadenitis, osteomyelitis and sepsis with a variety of organisms: Staphylococcus aureus, Burkholderia cepacia, Pseudomonas aeruginosa, Serratia marcescens, Aspergillus. Aspergillus nidulans is an organism that is almost a signature organism for CGD. In North-America, infections with Nocardia are common, less so in Europe. A deep-seated abscess such as a liver abscess should always alert to CGD and alternatively to a defect in the TIR pathway. Treatment of this complication needs long term antibiotic treatment, often in conjunction with steroids to dampen inflammation. An important note is that infections are much less symptomatic in children with CGD and have only mildly elevated leukocyte counts, CRP and fever. The granulomatous manifestation can occur in any organ system: skin, eye, gastrointestinal tract, urogenital tract. They are often responsive to steroid treatment, which should be considered in case of considerable inflammatory problems (e.g. urogenital obstruction due to granuloma).Lupuslike phenomena can also occur and should not defer the clinician’s attention from the infectious load. Most children do fine with antimicrobial prophylaxis (in the form of trimethoprim-sulfomethoxazole and itraconazole). However, there is a clear indication for HSCT early on given the important mortality and morbidity related to this disease. Especially in the context of a severe inflammatory or infectious manifestation, HSCT is the primary choice and the only option for definitive cure. A final important note on CGD is that female carriers of X-CGD can express the disease to variable degrees.

Figure 2. Algorithm for the differential diagnosis of defects in the phagocyte system.

Congenital defects of phagocyte number, function, or both

Pancytopenia, exocrine pancreatic insufficiencyChondrodysplasiaShwachman-Diamond (SBDS)

Structural heart defects, urogenital abnormalities, and venous angiectasias of trunks and limbsSevere congenital netropeniatype 4 (G6PC3)

Extramedullary hematopoiesis, bone marrow fibrosis, nephromegaly:SCNS (VPS45)

Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegalyGlycogen storage disease type 1b (G6PT1)

Retinopathy, developmental delay, facial dysporphismCohen sd (VPS13B)

Cardio-myopathy, growthretardatioin, XL Bart sd (TAZ)

Poikiloderma, myelodysplasia: Poikiloderma with neutropenia (C16orf57)

syndomic

Failure to thrive, partial albinism, hypogammagloulinemia: P14/LAMTOR2 def (ROBLD3/LAMTOR2)

Microcephaly, hypoglycemia, hypotonia, ataxia, seizures cataracts, IUGR 3-methylglutaconic aciduria, type VII (CLBP)

Yes without anti-PMN auto abs)

not syndromic

symptomatic asymptomatic

1 CBC/twiceweekly x 4

cyclicvariations ?

transient NP of infancy

virus inducedNP

Yes: cyclic neutropenia

(ELANE)

No: severe congenital

neutropenia(SCN)

AD+/- myelodysplasia SCN1 (ELANE)B/T : SCN2 (GFI1)

AR Kostmann (HAX1)JAGN1 def (JAGN1)G-CSF receptor def (CSF3R)

XL-Neutropenia/ myelodysplasia(WAS)

neutropenia ? no

Dihydrorhodamine assay

normal

LAD : Skin infections evolve to large ulcers

WBC > 25000

LAD I (ITGB2)Delayed cord separation withomphalitis +++, skin infections evolveto large ulcers, no pus formation, lackof inflammation is observed in infectioin area. Periodontitis leads toearly loss of teeth, CD18 def (CMF) severity of the disease correlates withthe degree of deficiency in CD18 leukocytosis with neutrophilia (WBC 20,000-150,000 with 60-85% neutrophils)

LAD II (SLC35C1)Extremely rare, recurrent infectionswith marked leukocytosis. Severe growth delay and severe intellectualdeficit. Facial dysmorphism(depressed nasal bridge). Severe periodontitis later in life. Bombay blood group. Infections: rarely life threatening. Patients may live toadulthood

LAD III (FERMT3)Severe bacterial infections and severe bleeding disorder. Leukocytosis withneutrophilia platelet aggregationassay.

Susceptibility tomycobacteria, papilomaviruses, histoplasmosis, alveolar proteinosis, myelodysplasia/AML/ CMML . Low NK.GATA2 (GATA2)

abnormal

CGD:Early onset of severe and recurrentinfections affecting initially thenatural barriers of the organism(lungs, lymph nodes, skin), andeventually inner structures (liver, spleen, bones, brain, and +++ hepatic abscess).

Gralulomata obstructingrespiratory, urinary or gastrointestinal tracts. Inflammatory bowel disease(Crohn’s like disease) and perianaldisease : up to 30 %

Pathogens: typically catalasenegative bacteria (Staph. Aureusand gram-negative bacilli, Aspergillus, Candida); other: Burkholderia cepacia, Chromobacterium violaceum, Nocardia, and invasive serratiamarcescens. In developingcountries, BCG : adverse effects in up to 20 %.

Microscopic granulomas.Inflammatory

XL CGD: CYBB (gp91phox)

AR CGD :NCF1 (p47phox)CYBA (p22phox)NCF4 (p40phox)NCF2 (p67phox)


State of the Art

3. We will only briefly mention Leukocyte Adhesion Deficiency, of which 3 distinct forms have been described. The main presenting sign of LAD-1 and LAD-3 is delayed healing of the umbilical cord with recurrent skin infections in the absence of pus formation. LAD-3 adds to this a bleeding disorder. Blood analysis typically shows very high neutrophil counts as the basic problem lies in an impairment of the egression of neutrophils from the blood stream to the site of infection. The only cure is HSCT early on as most children die prior to the age of 2y due to infection. LAD-2 represents another type of disease with mental retardation, short stature and periodontitis. Here the defect is due to a deficient glycosylation.

Acknowledgement: The author thanks Ms. Jo Vencken for preparation of the Figures adapted from “The 2015 IUIS Phenotypic Classification for Primary Immunodeficiencies. Bousfiha A, Jeddane L, Al-Herz W et al. J Clin Immunol. 2015 Nov;35(8):727-38”

1. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Toubiana J, Okada S, Hiller J et al. Blood. 2016 Jun 23;127(25):3154-64

2. The 2015 IUIS Phenotypic Classification for Primary Immunodeficiencies. Bousfiha A, Jeddane L, Al-Herz W et al. J Clin Immunol. 2015 Nov;35(8):727-38.

3. Host genetics of severe influenza: from mouse Mx1 to human IRF7. Ciancanelli MJ, Abel L, Zhang SY, Casanova JL. Curr Opin Immunol. 2016 Feb;38:109-20.

4. Infectious disease. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency. Ciancanelli MJ, Huang SX, Luthra P et al. Science. 2015 Apr 24;348(6233):448-53.

5. Inborn errors underlying herpes simplex encephalitis: From TLR3 to IRF3. Zhang SY, Casanova JL. J Exp Med. 2015 Aug 24;212(9):1342-3.

6. Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity. Bustamante J, Boisson-Dupuis S, Abel L, Casanova JL. Semin Immunol. 2014 Dec;26(6):454-70.

7. A Comprehensive Approach to the Management of Children and Adults With Chronic Granulomatous Disease. Thomsen IP, Smith MA, Holland SM, Creech CB. J Allergy Clin Immunol Pract. 2016 May 10. doi: 10.1016/j.jaip.2016.03.021. [Epub ahead of print]

8. Chronic granulomatous disease. Holland SM. Hematol Oncol Clin North Am. 2013 Feb;27(1):89-99. Doi: 10.1016 Pathogenic mechanisms and clinical implications of congenital neutropenia syndromes Hauck F, Klein C. Curr Opin Allergy Clin Immunol. 2013 Dec;13(6):596-606.

9. Leukocyte adhesion deficiencies. Hanna S, Etzioni A. Ann N Y Acad Sci. 2012 Feb;1250:50-5.

10. Severe infectious diseases of childhood as monogenic inborn errors of immunity. Casanova JL. Proc Natl Acad Sci U S A. 2015 Dec 22;112(51):E7128-37.

11. Glynis Frans, KU Leuven, PhD Thesis. Unraveling defects in the human innate immune system Diagnosis of inherited disorders in the NF-κB pathway.

12. Nima Rezaei, Asghar Aghamomahammadi, Luigi Notarangelo. Eds. Primary Immunodeficiency Diseases. Definition, Diagnosis and Management. Springer.

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Children with DS are prone to the development of different medical problems due syndrome-specific predisposing factors. Together with the increasing life expectancy in individuals with DS, age-specific multidisciplinary health care will be mandatory to obtain maximum quality of life. The last years, effort is made to develop guidelines for the treatment of the potential (medical) problems in children with DS. The American Academy of Paediatrics (AAP) recommends guidelines for age-specific health supervision, based upon a multidisciplinary approach including several areas throughout childhood ¹. These guidelines also propose a systematic follow up for all children with DS, who are reviewed at least annually during whole childhood. Children with DS are predisposed to ENT problems due to both anatomical (midfacial hypoplasia, narrow nasopharynx, relative macroglossia, adenotonsillar hypertrophy) and functional factors (immature immune system, respiratory infections, hypotonia) 2, 3. A high prevalence of sleep problems including obstructive sleep apnea (OSA) and ear pathology is reported in literature. As such, ENT pathology may not be underestimated as part of the multidisciplinary approach in general health care, especially since it is often treatable and reversible. Early recognition and treatment may prevent negative impact on neurocognitive development.

Ear-nose-throat (ENT) follow-up in children with DSConform the guidelines for good clinical practice (corresponding to the AAP), children with DS are regularly seen at the ENT department as part of a multidisciplinary approach. Children enrolled at the multidisciplinary Down team of the Antwerp University Hospital with regular visits at the ENT department were eligible for inclusion. For all these children, at every visit detailed history was taken and a clinical examination performed. Otologic evaluation included microscopic evaluation of the tympanic membrane, tympanometry and audiometric evaluation according to the child’s age and cognitive abilities. Sleep problems were evaluated with a validated questionnaire (Child Sleep Habits Questionnaire (CSHQ)) and a full overnight polysomnography (PSG) was performed to exclude OSA (defined as an obstructive apnea/hypopnea index (oAHI) ≥ 2/h). Children with DS and OSA, and without previous UA surgery, were scheduled for a drug-induced sedation endoscopy (DISE) to evaluate the upper airway. If indicated, an adenotonsillectomy (AT) was performed during the same anaesthesia. After (surgical) treatment, a control PSG was scheduled to objectively evaluate treatment outcome.

Three main ENT topics were further analysed in children with Down syndrome, and discussed below.

Sleep problems in children with Down syndrome

Children with DS are at increased risk to develop general sleep problems, other than sleep-related breathing disorders, compared to normal developing children 4, 5. These sleep problems include difficulties in initiating and maintaining sleep, excessive daytime sleepiness and may adversely affect cognitive function, academic performance and behaviour. Validated questionnaires as the Child Sleep Habits questionnaire (CSHQ) may help to recognize and discuss sleep problems. The CSHQ was used to obtain prevalence numbers of sleep problems in children with DS, and to compare this with a reference population of normal developing children. Based upon the results of the CSHQ, children with DS were found to have a high prevalence of sleep problems (74%) compared to normal developing children (36%). Daytime sleepiness, sleep disordered breathing and parasomnias were significantly more reported in children with DS. No correlation between general sleep problems and underlying OSA was found, which indicates that parental history is not predictive for underlying sleep-disordered breathing.

Obstructive sleep apnea

Literature reports prevalences of OSA between 30 and 60% in children with DS ², compared to 0.7-2.0% in a general paediatric population. Due to the complexity of OSA in children with DS, the gold standard treatment of paediatric OSA (adenotonsillectomy (AT)) is often not curative (failure 30-50%) 6, 7. Recently, the use of drug-induced sedation endoscopy is introduced to define the level of upper airway (UA) collapse in paediatric OSA with the ultimate goal to increase success rate of treatment.Based upon PSG data in a large group of children with DS (n=122), we found a high prevalence of OSA (66%), mostly in the severe range (oAHI ≥ 10/h). Even in those with a negative history for sleep disordered breathing, more than half of the children presented with OSA. Younger children often had more severe OSA. No correlation was found between OSA severity and patient related factors (body mass index, age, gender) 8. During PSG, video registration was performed in 61 children and in 23% of them a unique sleep position (sleeping sitting of leaning forward with the head on the bed) was found. This unique sleeping position was

Down syndrome, an ENT perspective.

Mieke Maris ¹, Marek Wojciechowski ², Stijn Verhulst ², Paul Van de Heyning ², An Boudewyns ¹.

¹ ENT Department of Otorhinolaryngology, Head and Neck surgery, Antwerp University Hospital, Edegem, Belgium² Department of paediatrics, Antwerp University Hospital, Edegem, Belgium

[email protected]

Health care in children with Down syndrome



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significantly more prevalent in the children without OSA. This may indicate that unique sleeping positions could be a protective mechanism against upper airway obstruction during sleep.Adenotonsillectomy resulted in a significant improvement in oAHI, yet 47.1% of the children had persistent disease (oAHI ≥ 5/h), independent of patient related factors 9. Drug-induced sedation endoscopy (DISE) was investigated as a tool to assess upper airway collapse in children with DS and OSA, and to evaluate outcome results of DISE directed treatment. In most children UA collapse at the level of adenoids/tonsils was found (75%) and only a minority presented with tongue base collapse (7%). A high percentage of surgically naive children with DS (85%) presented with a multilevel collapse (outside the level of the adenoids and/or tonsils), which might explain the high percentage of persistent disease after AT. Although, no significant association between pre-operative DISE findings and persistent OSA was found.

Otitis media with effusion

Children with DS show a high prevalence of hearing problems, otitis media with effusion (OME) is the most common cause 10. Even mild hearing loss may result in delayed speech and language acquisition, especially in children with a developmental disorder as Down syndrome. In literature age-specific prevalence rates are not well defined, and the natural course of OME is not known. We aimed to define age-specific prevalence numbers of OME in children with DS. A retrospective cross-sectional study in 107 children with DS revealed a high prevalence of OME at the age of 1 year (66%) and 6-7 years old (60%). A declining trend is seen at older age. Bilateral OME was associated with significant hearing loss 11.

Conclusions and future perspectivesENT pathology is common in children with DS, and a systematic ENT follow-up as part of a multidisciplinary approach is assumed to contribute to a better quality of life in children with DS. A high prevalence of both sleep problems and OSA was found in children with DS, compared to a general paediatric population. Parental history for sleep-disordered breathing was not predictive for underlying OSA, which underscores the importance of performing a polysomnography (PSG) in all children with DS. Since younger children often present with more severe OSA, question arises whether polysomnography should be performed at younger age than the recommended age of 4 years by the AAP. Future age-specific prevalence rates may further address this question. In this study, almost half of the children with DS and OSA showed persistent disease after adenotonsillectomy based on PSG data. Drug-induced sedation endoscopy defined a multilevel upper airway collapse in the majority of the children, indicating complex upper airway disease. DISE-based findings may help treatment decision in case of persistent disease. A high prevalence of OME was found in children with DS, with a peak prevalence at the age of 1 year and 6-7 years old. Bilateral OME results in significant worse hearing. Early recognition and treatment is advised. Future studies evaluating the effect of ventilation tube placement on speech-and language development in children with DS and OME may contribute to the decision making in treating OME in children with DS.

1. Bull MJ, Committee on G. Health supervision for children with Down syndrome. Pediatrics 2011;128:393-406.

2. Shott SR. Down syndrome: common otolaryngologic manifestations. American journal of medical genetics. Part C, Seminars in medical genetics 2006;142C:131-40.

3. Chin CJ, Khami MM, Husein M. A general review of the otolaryngologic manifestations of Down Syndrome. International journal of pediatric otorhinolaryngology 2014;78:899-904.

4. Carter M, McCaughey E, Annaz D, Hill CM. Sleep problems in a Down syndrome population. Archives of disease in childhood 2009;94:308-10.

5. Breslin JH, Edgin JO, Bootzin RR, Goodwin JL, Nadel L. Parental report of sleep problems in Down syndrome. Journal of intellectual disability research : JIDR 2011;55:1086-91.

6. Donnelly LF, Shott SR, LaRose CR, Chini BA, Amin RS. Causes of persistent obstructive sleep apnea despite previous tonsillectomy and adenoidectomy in children with down syndrome as depicted on static and dynamic cine MRI. AJR. American journal of roentgenology 2004;183:175-81.

7. Shete MM, Stocks RM, Sebelik ME, Schoumacher RA. Effects of adeno-tonsillectomy on polysomnography patterns in Down syndrome children with obstructive sleep apnea: a comparative study with children without Down syndrome. International journal of pediatric otorhinolaryngology 2010;74:241-4.

8. Maris M, Verhulst S, Wojciechowski M, Van de Heyning P, Boudewyns A. Prevalence of Obstructive Sleep Apnea in Children With Down Syndrome. Sleep 2015.

9. Maris M, Verhulst S, Wojciechowski M, Van de Heyning P, Boudewyns A. Outcome of adenotonsillectomy in children with Down syndrome and obstructive sleep apnoea. Archives of disease in childhood 2016.

10. Harigai S, Tanaka Y, Iino Y. Hearing level of otitis media with effusion in children with Down's syndrome. International journal of pediatric otorhinolaryngology;35:288-.

11. Maris M, Wojciechowski M, Van de Heyning P, Boudewyns A. A cross-sectional analysis of otitis media with effusion in children with Down syndrome. European journal of pediatrics 2014;173:1319-25.

REFERENCES:


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Childhood obesity has become a real pandemic. 42 million children and young adolescents worldwide are overweight or obese, according to recent publications 1-3. In Belgium, none less than 20% of children and adolescents are overweight and about 7% of them are obese 4. Unfortunately, the issue still isn’t getting the attention it deserves from clinicians and the scientific community. First of all, Childhood obesity is not a transient developmental phenomenon, but a chronic problem. More than half of the obese children become obese adults 5, 6. Secondly, Childhood obesity is associated with multiple medical and psychosocial co morbidities, such as coronary atherosclerosis, obstructive sleep apnoea syndrome, type II diabetes mellitus, depression, and decreased self-esteem. 7-11 In the long run, these account for 86% of deaths and 77% of disease burden in Europe. As a consequence, the cost of obese children not being treated optimally and growing up to obese adults is becoming immense for society; it was recently estimated to be no less than $19.000 (almost €17 000) per person 12.

Hence, a high BMI during childhood is associated with increased cardiovascular morbidity 13 and mortality 14 at adult age. This increased cardiovascular risk is linked to coronary atherosclerosis and its clinical consequences such as acute myocardial infarction and stroke. Endothelial dysfunction is the first step in the development of atherosclerosis and is defined as “an imbalance between vasodilating and vasoconstricting substances produced by (or acting on) endothelial cells” 15. The process of endothelial dysfunction develops in the entire vasculature: in both small resistance vessels (microvascular endothelial dysfunction) and large conduit arteries (macrovascular endothelial dysfunction).

Luckily, it seems to be reversible. In addition, adults with normal weight and normal exercise capacity but who were obese as a child carry the same risk for cardiovascular disease as adults who were normal weight as a child 16.

At the start of my PhD project on obesity-related endothelial dysfunction in children, studies had been primarily designed to investigate the vascular endothelium in obese adults. The arterial walls in obese adults, however, have often been exposed to cardiovascular risk factors over many decades. We aimed to investigate early vascular endothelial changes. To start with, we reviewed the literature on endothelial dysfunction in regard to its pathogenesis and discussed the various factors that could affect the vascular endothelium at a functional level in obese children. Many interacting factors, such as a low HDL cholesterol and hypertension, are already present in obese children, and negatively affect endothelial function. Yet, also new factors were discovered such as leptin, an adipokine that directly affects endothelial function 17. These factors mainly act on the activity of endothelial NO synthase (eNOS) and its end product NO which induces vasodilation by relaxation of vascular smooth muscle cells. For an overall summary of clinically important factors influencing endothelial function in childhood obesity and of methods available for assessing the degree of endothelial impairment, we kindly refer to this first review 18. However, in our project we wanted to go one step further and investigate how endothelial (dys)function in obese children is affected by mechanisms of endothelial damage and repair (vide infra).

Endothelial dysfunction in obese children: shifting the balance between endothelial damage and repair?

Luc Bruyndonckx 1, 2, 3, 4, Vicky Y Hoymans 1, 3, José Ramet 2, 4, Christiaan J Vrints 1, 3.

¹ Laboratory of Cellular and Molecular Cardiology, Department of Cardiology, University Hospital Antwerp, Edegem, Belgium² Queen Mathilde Mother and Child Centre, Antwerp University Hospital, Edegem;³ Cardiovascular diseases, Department of Translational Pathophysiological Research, University of Antwerp, Antwerp, Belgium4 Laboratory of Experimental Medicine and Paediatrics, University of Antwerp, Antwerp, Belgium

[email protected]

Introduction

AbstractDuring the past decade it has become clear that endothelial dysfunction, which is the earliest demonstrable step in the process of atherosclerosis, may serve as a major target for therapy and a surrogate endpoint in interventional studies which aim to reverse the detrimental effects of longstanding obesity in children. In this paper, we discuss novel diagnostic markers of impaired endothelial barrier integrity such as Endothelial Progenitor Cells (EPC), Circulating Angiogenic Cells (CAC) and Endothelial MicroParticles (EMCP) and their clinical significance. In particular, we discuss the results of an interventional study in obese children in which we evaluated the effects of diet and exercise on microvascular endothelial dysfunction and cell-based markers for endothelial damage and repair.

KeywordsChildhood Obesity - Endothelial Dysfunction –– Endothelial Progenitor Cells – Endothelial microparticles – Circulating Angiogenic Cells.



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Assessment of endothelial function in childrenEndothelial function can be assessed both at the large conduit vessels as well as at the small resistance vasculature. The most widely used technique to asses macrovascular function is called flow mediated dilation (FMD). For this assessment an ultrasound probe is placed on the brachial artery and the diameter is continuously registered. After 5 minutes baseline assessment, the brachial artery is occluded by inflating a sphygmomanometer to supra-systolic pressures during 5 minutes. After releasing the cuff, the resulting shear induced maximal vasodilation is registered. The ratio of maximal dilation to the baseline diameter reflects macrovascular endothelial function 19. However, recent research demonstrated that endothelial dysfunction develops earlier in the small resistance vessels (microvascular endothelial dysfunction) than at the macrovascular level 20. Assessment of microvascular endothelial function was simplified when the Endo-PAT was introduced (figure 1). This technique uses 2 probes placed on both index fingers 21. After a baseline assessment, the brachial artery is occluded using a sphygmomanometer, and the resulting vasodilation of the arterioles in the fingers is registered. Since we wanted to investigate the earliest functional changes in the endothelium, we decided to evaluate the endo-PAT technique for is use in children and adolescents. Together with our colleagues from Bern University, we reviewed the available literature, shared our experiences with the technique and published the first recommendations on how to perform endo-PAT measurements in children in a standardized fashion 22. Factors present in growing children were taken into account, such as pubertal development 23, 24, recurrent viral infections 25 and the higher variability in the time necessary to reach maximal dilation 26. This paved the way to optimise microvascular endothelial function assessment in obese and normal weight children.

Cell based markers for endothelial damage and repairDue to its location, between the blood and the vascular wall, the endothelium is continuously exposed to potentially harmful factors, such as cholesterol. When the endothelium is damaged, it releases small particles (0,5-1µm in size) 27. These endothelial microparticles (EMP) still carry markers of the parent cell (figure 2), allowing the quantification of EMP on multicolour flow cytometry 28. The Framingham Heart study studied 844 adults without a history of cardiovascular disease, and demonstrated that levels of circulating EMP strongly correlate with several cardiometabolic risk factors 29.The endothelium has limited self-repair capacity, as it is built up by terminally differentiated cells with low proliferative potential. However, in the late 90’s it

became clear that Endothelial Progenitor Cells (EPC) actively participate in repair of the endothelium. These progenitor cells are released by the bone marrow and migrate upon stimuli to loci of damaged endothelium. They take the place of lost endothelial cells. The mobilization of EPC into the blood stream is impaired in patients with cardiovascular risk factors. In obese adults, lower numbers of these EPC have been detected 30. Obesity occurs to be a more prominent predictor of low EPC level than other cardiovascular risk factors. Vice versa, weight-loss has been associated with an increase in EPC count and with improved macrovascular endothelial function 30. Counterintuitively, Jung et al reported an increased number of circulating EPC in obese children 31. Methodological issues, raised by the lack of EPC assay standardization and phenotypic definition, might have accounted for the unexpected higher level of circulating EPC in the study by Jung et al. Guidelines to perform EPC quantification in an uniform fashion were set forth by our lab 32, including specific recommendations for children to increase sample volumes and taking mild viral infections into account as possible confounder.Besides EPC, Circulating Angiogenic Cells (CAC) also help to restore endothelial integrity. CAC are hematopoietic cells 33 that contribute to endothelial repair by attracting circulating EPC in the blood and by stimulating their integration into the injured endothelium via the secretion of angiogenic growth factors. In addition to the lower number of circulating CAC, the migratory capacity of CAC is impaired in obese adults 34. CAC in obese adults are further resistant to leptin associated pro-angiogenic effects, though this resistance can be reversed by weight loss 35. The adipokine leptin is mainly known for its role in regulating human energy homeostasis and appetite 36, yet it is also able to improve the migratory activity of CAC in normal-weight adults 37.

Balance between endothelial damage and repair in obese childrenFor a first study, 57 obese (15.2 ± 1.4 years) and 30 normal-weight children (15.4 ± 1.5 years) were recruited 38. Microvascular endothelial function was significantly impaired in the obese children and inversely correlated with body

mass index Z scores and systolic blood pressure. EMPs were present at low levels in normal-weight children, but were significantly higher in obese children. EMP numbers correlated inversely with endothelial function. The number of EPCs was significantly lower in obese children if compared with normal-weight children and numbers correlated with endothelial function. Yet EPC and EMP are not just innocent bystanders. Multiple linear regression analysis revealed that systolic blood pressure and numbers of circulating EPCs and EMPs are independent determinants of endothelial function in children. Our results suggested that there is an imbalance between endothelial damage and repair in obese children in favour of the former (figure 3). In a subsequent study, we provided the first evidence that CAC in obese children are functionally impaired as they demonstrated a reduced migratory capacity but, in contrast to CAC in obese adults, are not yet resistant to the proangiogenic actions of leptin 39.

Reversibility of endothelial dysfunctionThe next question that arose was whether an intensive treatment would be able to improve microvascular endothelial function in obese children. For this project, we collaborated with the Zeepreventorium, that offers a residential treatment program for childhood obesity, which has been described earlier in detail 40. An ambulant ly treated cohort of obese children was enrolled as a control group to allow instant comparison of endothelial outcome parameters. This study demonstrated for the first time that 10 months of residential treatment consisting of diet and supervised exercise training is able to significantly improve microvascular endothelial function in obese children. From our data, it became apparent that it is probably more difficult to tackle microvascular than macrovascular endothelial dysfunction, as the latter can be reversed by as little as 6 weeks of exercise training 41. In addition, a biphasic response was noted for markers of endothelial damage and repair, with an initial significant increase in circulating EPC at 5 months, followed by a marked reduction in EMP at 10 months 42. The higher numbers of EPC at 5 months most likely reflect active repair of the endothelium. EPC numbers increase during a period of physical training 43. However, once there is less endothelial damage (i.e. Lower EMP levels after 10 months of treatment) those higher numbers of EPC might be no longer necessary.

Figure 1: Endo-PAT measurement in healthy volunteer

Probes are placed on both index fingers and a sphygmomanometer is used to occlude the brachial artery in the non-dominant arm


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Figure 3: balance between endothelial damage and repair in obese adolescents and healthy subjects

Figure 2 : endothelial damage and repair

In obese children with endothelial dysfunction and imbalance between endothelial damage and repair is noted with increased endothelial damage (reflected in higher number of EMP) and a reduced endothelial repair capacity (with lower numbers of EPC and impaired function of CAC).

A. Endothelial damage: when circulating factors damage the endothelium EMP are released in the circulatingB. Endothelial repair mechanisms: firstly CAC migrate to loci of damaged endothelium and secrete angiogenic growth factors. These growth factors stimulate the

release of EPC from the bone marrow and act as chemo attractants. Finnaly EPC take the place of lost endothelial cellsC. LegendThis figure was created using Servier medical art.

Future perspectivesThe current guidelines for the treatment of childhood obesity still mainly focus on weight loss or weight stabilisation and reduction in BMI through growth 44. However, the main goal should be long-term reduction in cardiovascular morbidity and mortality. Endothelial function could be used as a surrogate marker to objectify the effects of treatment programs. EPC, CAC and EMP could provide additional information about endothelial status, and be used to estimate the balance between injury and repair.

AcknowledgementsWe wish to honor prof. Viviane Conraads (°12/12/2013) who initiated this project and was supervisor, yet passed away too early.

Financial DisclosureThe authors have no financial relationships relevant to this article to disclose. This work was supported by the University Research Fund (BOF-ID) of the University of Antwerp to Drs Conraads, Vrints, Ramet, and Bruyndonckx (grant 24585) and by the Belgian Hypertension Committee Award 2010.

Luc Bruyndonckx and Vicky Hoymans wrote the first draft of manuscript. Luc

Bruyndonckx, Vicky Hoymans, José Ramet and Christiaan Vrints critically reviewed the manuscript. All authors approve the submitted version.


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31. Jung C, Fischer N, Fritzenwanger M, Thude H, Ferrari M, Fabris M, et al. Endothelial progenitor cells in adolescents: impact of overweight, age, smoking, sport and cytokines in younger age. Clinical research in cardiology : official journal of the German Cardiac Society. 2009;98:179-88.

32. Van Craenenbroeck EM, Van Craenenbroeck AH, van Ierssel S, Bruyndonckx L, Hoymans VY, Vrints CJ, et al. Quantification of circulating CD34(+)/KDR(+)/CD45(dim) endothelial progenitor cells: Analytical considerations. International journal of cardiology. 2012.

33. Medina RJ, O’Neill CL, O’Doherty TM, Knott H, Guduric-Fuchs J, Gardiner TA, et al. Myeloid angiogenic cells act as alternative M2 macrophages and modulate angiogenesis through interleukin-8. Molecular Medicine. 2011;17:1045.

34. MacEneaney OJ, Kushner EJ, Van Guilder GP, Greiner JJ, Stauffer BL, DeSouza CA. Endothelial progenitor cell number and colony-forming capacity in overweight and obese adults. Int J Obes. 2008;33:219-25.

35. Heida N-M, Leifheit-Nestler M, Schroeter MR, Müller J-P, Cheng I-F, Henkel S, et al. Leptin Enhances the Potency of Circulating Angiogenic Cells Via Src Kinase and Integrin αvβ5 Implications for Angiogenesis in Human Obesity. Arteriosclerosis, thrombosis, and vascular biology. 2010;30:200-6.

36. Friedman JM. The function of leptin in nutrition, weight, and physiology. Nutr Rev. 2002;60:S1-14; discussion S68-84, 5-7.

37. Schroeter MR, Leifheit M, Sudholt P, Heida N-M, Dellas C, Rohm I, et al. Leptin enhances the recruitment of endothelial progenitor cells into neointimal lesions after vascular injury by promoting integrin-mediated adhesion. Circulation research. 2008;103:536-44.

38. Bruyndonckx L, Hoymans VY, Frederix G, De Guchtenaere A, Franckx H, Vissers DK, et al. Endothelial progenitor cells and endothelial microparticles are independent predictors of endothelial function. The Journal of pediatrics. 2014;165:300-5.

39. Bruyndonckx L, Hoymans VY, Frederix G, Van Ackeren K, De Guchtenaere A, Franckx H, et al. Circulating Angiogenic Cells from obese children do not display leptin resistance. International journal of cardiology. 2014;174:881-3.

40. Braet C, Tanghe A, Bode PD, Franckx H, Winckel MV. Inpatient treatment of obese children: a multicomponent programme without stringent calorie restriction. European journal of pediatrics. 2003;162:391-6.

41. Woo KS, Chook P, Yu CW, Sung RYT, Qiao M, Leung SSF, et al. Effects of Diet and Exercise on Obesity-Related Vascular Dysfunction in Children. Circulation. 2004;109:1981-6.

42. Bruyndonckx L, Hoymans VY, De Guchtenaere A, Van Helvoirt M, Van Craenenbroeck EM, Frederix G, et al. Diet, exercise, and endothelial function in obese adolescents. Pediatrics. 2015;135:e653-61.

43. Walther C, Gaede L, Adams V, Gelbrich G, Leichtle A, Erbs S, et al. Effect of Increased Exercise in School Children on Physical Fitness and Endothelial Progenitor Cells: A Prospective Randomized Trial. Circulation. 2009;120:2251-9.

44. Spear BA, Barlow SE, Ervin C, Ludwig DS, Saelens BE, Schetzina KE, et al. Recommendations for Treatment of Child and Adolescent Overweight and Obesity. Pediatrics. 2007;120:S254-S88.


Belgian Journal of Paediatrics

New publication guidelines. ISSN 2466-8907

Aims and scope The Belgian Journal of Paediatrics is published by the Belgian Society of Paediatrics.

The Belgian Journal of Paediatrics publishes original articles, special reports, review articles, short communications, case reports, letters to the editor, and commentaries

on all aspects of paediatrics.

The Belgian Journal of Paediatrics is published quarterly.

EditorsEditors: S. Cadranel, M. Raes

Editorial board: S. Cadranel, M. Raes, N. Francotte, M. Wojciechowski

Editorial office: UZ Leuven, Herestraat 49, 3000 Leuven

Publisher: H Consult, Chaussée de Bruxelles, 94b, 1410 Waterloo

Owner: Belgische Vereniging voor Kindergeneeskunde – Société Belge de Pédiatrie

Instructions for authors

Submission information

Manuscripts must be submitted in Word (single-spaced) and sent by e-mail to the editor at [email protected]. All manuscripts considered for publication undergo

peer review. In order to be eligible for peer review manuscripts must comply with the guidelines described in the instructions for authors. Manuscripts not prepared

according to the instructions for authors will be returned to the author(s) without review.

A submitted manuscript must be an original contribution not previously published (except as an abstract, as part of a published lecture or a thesis, or with authorization

of the publisher). Each person listed as an author is expected to have participated in the study to a significant extent. Although the editors and reviewers make every

effort to ensure the validity of published manuscripts, the final responsibility rests with the authors, not with the Journal, its editors, or the publisher.

Language: the preferential use of English (UK) is strongly encouraged. Papers can also be submitted in French or Dutch.

Abstracts should always be in English and limited to 250 words. Do not cite references in the abstract.

Text: Organize the manuscript into four main headings: Introduction, Materials and Methods, Results, and Discussion. Define abbreviations at first mention in text and

in each table and figure.

Data Analysis: Description of data analyses should provide the specific methods used, their rationale, the underlying assumptions, whether data met those

assumptions, and how any missing data were handled.

Abbreviations should be defined at first mention in the text and used consistently thereafter.

Units of measurement and laboratory values: measurements of length, height, weight, and volume should be reported in metric units (meter, kilogram, or liter)

or their decimal multiples. Temperatures should be in degrees Celsius. Blood pressures should be in millimeters of mercury. Hematologic, clinical chemistry, and other

measurements can be provided in local or International System of Units (SI) with normal values between brackets.



Belgian Journal of Paediatrics Editorial Policy

Drugs and other products: non-proprietary names of drugs or other products should be used, unless a specific trade name is essential for discussion.

Eponyms and acronyms: eponyms should be used in their non-possessive form (e.g. Down syndrome and not Down’s syndrome). Acronyms should be avoided; if

this is not possible they should be fully explained when first used.

Tables should be submitted as separate files in Word or embedded Excel. Each table must have a title. Screen captured tables are not allowed.

Figures should be submitted as separate files in JPEG format. The resolution should be preferably 600 DPI. Each figure must have a legend. Legends should be typed

on a separate manuscript page, directly following the reference list.

Patient privacy and informed consent: it is the author's responsibility to ensure that a patient's privacy is carefully protected and to verify that any experimental

investigation with human subjects reported in the manuscript was performed according to all the guidelines for experimental investigation with human subjects

required by the institution(s) with which all the authors are affiliated.

Permissions: Authors must submit written permission from the copyright owner (usually the publisher) to use direct quotations, tables, or illustrations that have

appeared in copyrighted form elsewhere, along with complete details about the source.

Footnotes can be used to give additional information. Footnotes should be numbered consecutively.

References: authors are responsible for the accuracy of the cited references. References must be numbered sequentially as they appear in the text. Reference

numbers in the text must use superscript. Separate by a comma if more than one reference is cited, for example 1, 2, 3. For sequences of consecutive numbers the first

and last number of the sequence should be separated by a hyphen, for example 1-4. Only published papers or papers in press should be included in the reference list.

Personal communications or unpublished data must be cited in parentheses in the text with the author’s names, the source and year.

The reference list, numbered in the order of mention in the text, must appear at the end of the manuscript. If there are 6 or fewer authors or editors they must all be

listed; if there are 7 or more, the first 6 should be listed and ‘et al.’ added. Refer to the List of Journals Indexed in Index Medicus for abbreviations of journal names,

or access the list at http://www.nlm.nih.gov/archive/20130415/tsd/serials/lji.html.

References must follow the Vancouver style; examples:

For journal articles

I. Rautava S, Lu L, Nanthakumar NN, et al. TGF-ß2 induces maturation of immature human intestinal epithelial cells and inhibits inflammatory cytokine responses

induced via the NF-κB pathway.

J Pediatr Gastroenterol Nutr 2012; 54:630-8.

Kramarz P, DeStefano F, Gargiullo PM, Chen RT, Lieu TA, Davis RL, et al. Does influenza vaccination prevent asthma exacerbations in children?

J Pediatr 2001; 138:306-10.

For Articles in Press (online)

Hellems MA, Gurka KK, Hayden GF. A review of The Journal of Paediatrics: The first 75 years.

J Pediatr (2008). doi:10.1016/j.jpeds.2008.08.049.

For books

1. Ming SC, Goldman H. Pathology of the gastrointestinal tract. 2nd ed. Baltimore: Williams and Wilkins; 1998.

2. Virginia Law Foundation. The medical and legal implications of AIDS. Charlottesville (VA): The Foundation; 1987.

For chapters in books

1. Conners F. Phonological working memory difficulty and related intervention.

In: S.Buckley, and Rondal J.A. (ed.) Speech and language intervention in Down syndrome. London: Whurr 2003: 31-48

For websites

1. American Medical Association [homepage on the Internet]. Chicago: The Association; c1995-2002 [updated 2001 Aug 23; cited 2002 Aug 12].

AMA Office of Group Practice Liaison; [about 2 screens]. Available from: http://www.ama-assn.org/ama/pub/category/1736.html

Acknowledgements should be placed in a separate section after the conclusion.

http://www.nlm.nih.gov/archive/20130415/tsd/serials/lji.html.

http://www.ama-assn.org/ama/pub/category/1736.html



Title page: a title page should accompany all submissions and provide following information:

a. Complete manuscript title

b. Authors’ full names, in order first name (given name) then last name (family name), and affiliations

c. Name and address for correspondence, including fax number, telephone number, and e-mail address

d. The contribution of each author (see authorship criteria in the editorial policy)

e. Up to five keywords

f. The word count of the manuscript body (excluding abstract, keywords, references and figure legends), number of figures and number of tables

g. A statement that the manuscript has not been and will not be submitted to any other journal while it is under consideration by the Belgian Journal of Paediatrics

h. If the article reports a clinical trial: the registration number and the site of registry

Patient information: a written informed consent for publication of any information possibly identifying patients should be added as a separate page.

Disclosure of potential conflicts of interest: each author should submit a separate filled-in ICMJE form for disclosure of potential conflicts of interest (downloadable

at http://www.icmje.org/conflicts-of-interest/).

Article typesOriginal Articles: original articles are full-length reports of original research. Authors should aim for accuracy, clarity, and brevity. Long introductions, repetition of

data among tables, figures, and the text, and unfocused discussions should be avoided. Include an abstract of no more than 250 words. No more than 50 references

permitted.

Review Articles: review articles are usually solicited by the Editorial Board. However, unsolicited reviews of exceptional interest will also be considered. Reviews

should be balanced and unbiased. Include an abstract of no more than 250 words.

Short Communications: brief reports on topics relevant to the Belgian Journal of Paediatrics reader and preliminary reports of original studies of relevant scientific

importance. Short Communications must not exceed 1500 words (excluding the title, author names, abstract and references), 1 table and/or 1 figure, and no more

than 8 references. Include an abstract of 100 words or less.

Case Reports: case reports must not exceed 1500 words (excluding the title, author names, abstract and references), and may include up to three tables and figures

and no more than 8 references. Include an abstract of 100 words or less.

Letters to the Editor: letters should be brief (less than 250 words and 3 references), and will be published at the discretion of the editor.

After acceptanceCorresponding authors will receive electronic page proofs to check the copy-edited and typeset article before publication. Portable document format (PDF) files of

the typeset pages and support documents will be sent to the corresponding author by e-mail. It is the author’s responsibility to ensure that there are no errors in the

proofs. Changes that have been made to conform to journal style will stand if they do not alter the authors' meaning. Only the most critical changes to the accuracy of

the content will be made. The publisher reserves the right to deny any changes that do not affect the accuracy of the content. Proofs must be checked carefully and

corrections returned within 1 week of reception.

Copyright: by accepting publication in the Belgian Journal of Paediatrics authors automatically transfer copyright to the journal. Authors will receive a PDF file for

personal use only.

Reprints: reprints are available for members of the Belgische Vereniging voor Kindergeneeskunde – Société Belge de Pédiatrie from the website of the society at

http://bvk-sbp.be.

http://www.icmje.org/conflicts-of-interest/

http://bvk-sbp.be/



Editorial policyEditorship: the editors have full authority over the editorial content of the Journal and the timing of publication of that content.

Authorship criteria: Authors should meet the criteria for authorship according to the "Uniform Requirements for Manuscripts Submitted to Biomedical Journals:

Writing and Editing for Biomedical Publication" available at www.icmje.org. Only persons that have substantially contributed to all of the following are considered as

authors: conception and design, acquisition, analysis and interpretation of data; drafting the article or revising it critically; final approval of the version published. The

first and, if different, the corresponding author should declare on the title page that these criteria have been satisfied.

Persons who have contributed to the study or manuscript but who do not fulfil the criteria for authorship are to be listed under a heading ‘acknowledgments’. Financial

and material support should also be acknowledged.

Any change in authors after initial submission must be approved by all authors and must be explained to the Editor. The Editor may contact any of the authors and / or

contributors to verify whether they agree to any change.

The authors are fully responsible for the propositions and statements in their article. Neither the editors, editorial board and publisher of the TBK-JPB nor the executive

board of the Belgian Paediatric Society are responsible for mistakes or omissions

Ethical standards: human subjects research requires ethics committee approval. This should be documented in the ‘methods’ section of the paper. No information

possibly identifying patients should be included in the paper, unless the information is essential for scientific purposes and a written informed consent for publication

was obtained. This should be added as a separate page to the manuscript. Even when consent was given, identifying details should be omitted if not essential. Special

attention should be given to patient’s images, names, initials, hospital numbers. The registration number and the site of registry of clinical trials should be provided on

the letter of submission.

Duplicate or prior publication: only original manuscripts can be accepted that have not been published before (except in the form of an abstract, as part of a

published lecture or a thesis, or with authorization of the publisher).

Reproducing material from other sources: any written or illustrative material that has been or will be published elsewhere must be duly acknowledged and accompanied

by the written consent of the copyright holder.

The articles published in Belgian Journal of Paediatrics can be published in other journals with authorization of the editors.

Negative studies:the Belgian Journal of Paediatrics agrees with the International Committee of Medical Journal Editors statement regarding the obligation to publish

negative studies.

Peer review: all received papers will be peer reviewed by 2 reviewers designated by the editors. After review decision will be made to reject, accept as such or with

minor or major revisions. The reviewers’ names will be blinded to the authors. Revised manuscripts will be submitted again to the reviewers. The editors are responsible

for the final decision to accept or reject a manuscript. Authors will be notified about the decision and, if the manuscript is accepted, the timing of publication.

Advertising: advertisers are not allowed to influence or modify the content of accepted articles before publication. Advertisement of products like alcohol, tobacco

or products known to be harmful for children’s health are not allowed in the journal. Editors have the final authority to accept advertisements in each published issue

of the journal. Each advertisement is clearly identified as such and is not inserted in the flow of an article. The Belgian Society of Paediatrics oversees the advertising

policy of the journal.

http://www.icmje.org/

belgian journal of paediatrics · belgian journal of paediatrics • 2016 - vol. 18 - nr.3 223...

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