Primary ciliary dyskinesia (PCD), cystic fibrosis (CF), and chronic obstructive airway disease are characterized by neutrophilic inflammation in the lungs. In CF and chronic obstructive airway disease, improper functioning of neutrophils has been demonstrated. We hypothesized that the pulmonary damage in PCD might be aggravated by abnormal functioning neutrophils either as a primary consequence of the PCD mutation or secondary to chronic inflammation. We analyzed chemotactic responses and chemoattractant receptor expression profiles of peripheral blood neutrophils from 36 patients with PCD, 21 healthy children and 19 healthy adults. We stimulated peripheral blood monocytes from patients and healthy controls and measured CXCL8 and IL-1β production with ELISA. PCD neutrophils displayed reduced migration toward CXCR2 ligands (CXCL5 and CXCL8) in the shape change, microchamber and microslide chemotaxis assays, whereas leukotriene B4 and complement component 5a chemotactic responses were not significantly different. The reduced response to CXCL8 was observed in all subgroups of patients with PCD (displaying either normal ultrastructure, dynein abnormalities or central pair deficiencies) and correlated with lung function. CXCR2 was downregulated in about 65% of the PCD patients, suggestive for additional mechanisms causing CXCR2 impairment. After treatment with the TLR ligands lipopolysaccharide and peptidoglycan, PCD monocytes produced more CXCL8 and IL-1β compared to controls. Moreover, PCD monocytes also responded stronger to IL-1β stimulation in terms of CXCL8 production. In conclusion, we revealed a potential link between CXCR2 and its ligand CXCL8 and the pathogenesis of PCD.

Patients with Primary Ciliary Dyskinesia (PCD) suffer from recurrent upper and lower airway infections due to defects in the cilia present on the respiratory epithelium. Since chronic inflammatory conditions can cause changes in innate immune responses, we investigated whether monocytes isolated from the peripheral blood of pediatric PCD patients respond differently to inflammatory stimuli, compared to monocytes from healthy children and adults. The receptor for C5a (C5aR) was upregulated in PCD, whereas expression levels of the leukocyte chemoattractant receptors CCR1, CCR2, CCR5, BLT1 and FPR1 on PCD monocytes were similar to those on monocytes from healthy individuals. Also in vitro migration of PCD monocytes towards the ligands of those receptors (CCL2, fMLP, C5a and LTB4) was normal. Compared to healthy children, PCD patients had a higher percentage of the non-classic monocyte subset (CD14+CD16++) in circulation. Finally, PCD monocytes produced higher levels of pro-inflammatory cytokines (IL-1β and TNF-α) and chemokines (CCL3, CCL5, CCL18 and CCL22) in response to LPS, peptidoglycan and/or dsRNA stimulation. These data suggest that monocytes might exacerbate inflammatory reactions in PCD patients and might maintain a positive feedback-loop feeding the inflammatory process.

Background: A poorly performed inhalation technique is a well-known problem in adult patients but it is less documented in paediatric patients. Aim: This study aimed to evaluate the proper use of pressurized metered dose inhalers (pMDI) and dry powder inhalers (DPI) in children and their parents. Method: Thirty-nine children with chronic respiratory disease and already under inhalation therapy for at least three months were recruited prospectively during routine clinics. These children had received a training when treatment was started. A specific questionnaire evaluated their knowledge regarding the inhaled treatment and inhalation technique. The inhalation manoeuver was divided in maximum 17 steps and each step was assessed separately (score of 0 (=not performed) to 2 (=perfectly performed)). Results: Children (20F/19M) were 4.8±4.9 years old. Eighty seven per cent used a pMDI, 64% of whom with an aerosol chamber. Fifty six and 26% of children did not know the medication name and the colour of the device, respectively. The steps of the manoeuver were incorrectly or not performed in 9% and 27% of children using a pMDI. This proportion was similar (8% vs 31%) with the use of an aerosol chamber. The manoeuver was correct in 83% of steps for children using DPI. No error was detected for 50, 73 and 74% of children using pMDI, pMDI + chamber and DPI, respectively. Conclusion: The knowledge and technique of inhalation therapy is imperfect in children even after a routine education.

L’annee 2015 en pneumologie fut une nouvelle fois riche en nouveautes. Nous vous en proposons ici une liste non exhaustive par secteur d’activites. Elles concernent tant les aspects physiopathologiques notamment dans le syndrome des apnees du sommeil, que diagnostiques ou curatifs. Pour les premiers, citons les nouvelles valeurs de reference en spirometrie, l’apport des cryobiopsies dans les pathologies interstitielles diffuses, l’evaluation des bronchectasies de l’adulte, ... Pour les seconds, nous avons retenus pour vous les progres therapeutiques medicamenteux ou non dans l’asthme, la fibrose pulmonaire idiopathique, l’emphyseme, le cancer bronchique, …

Background CF is the leading cause of BE in affluent countries and overall it is clearly the most threatening one. Objective To compare outcomes in children with CF and children with non CF BE. Methods 4 Belgian academic Paediatric Pulmonology Units listed all children with non CF BE under care in 2011. From electronic medical files, they then extracted data concerning the 20 first children (by alphabetical order) meeting the following criteria: non-CF BE (CT), 6– Results Main etiologic diagnoses in Group A (n = 80) were PCD (29%), idiopathic BE (21%), immune deficiency (16%), post-infectious (11%), bronchiolitis obliterans (10%), aspiration (6%). Mean BMI (Z score) (±SD) were similar in both groups (A: −0.23±1.19, B: −0.47±1.03, p = 0.18). FVC and FEV1 (% pr, GLI) were lower in group A (FVC: 88.3±19.1 vs 95.9±12.5, p 1 y were available for 62 children with non CF BE (mean duration: 4.1 y). Over this period, mean spirometric and anthropometric outcomes did not decline. Conclusion At a mean age of 11 y, spirometric data of children with CF are more favorable than those of children with non CF BE, suggesting the latter could benefit from the CF model of care.

Background In Belgium in 2011, 35% of the 15–29 years age group were regular smokers. No information is available about epidemiology of smoking by CF patients in Belgium. Aims To identify active and passive smokers in the Belgian CF patients, to investigate the characteristics of addiction of active CF smokers. Methods Active and passive smokers were identified by means of urinary cotinine (UC) >100 ng/ml, measured by HPLC. Patients with positive UC were asked to meet with a tabacologist, to evaluate their expired CO, their physical, psychological and behavioural addiction to nicotine, and their HAD score. Results Preliminary analysis of 351 patients with complete data sets did not disclose any patient with positive UC before age 19.5. Overall, 30 out of 706 patients (4.5%, 78.8% of target) had a positive UC; 17 met the tabacologist (12 active smokers, 5 passive smokers). Most active smokers (28±10 y) were males (10/12). Mean UC of active smokers was 863±464 ng/ml, mean expired CO was 13.3±7.6 ppm, Fagestrom score was 4.5±3. Almost all active smokers (11/12) had attempted at least once to quit smoking and 5/12 (41%) smoked also cannabis. UC of active smokers was higher in patients with low SE status (1270 vs 747 ng/ml, p=0.04) and correlated with anxiety (R = 0.82, p=0.009). All smoking patients wished to receive specific help for smoking cessation at their CF centre. Conclusion Active or passive exposure to cigarette smoke was present in at least 4–5% of CF patients. Smoking cessation expertise should be available at CF reference centres.

The relationship between transhiatal protrusion of gastric mucosa, acid reflux and recurrent bronchitis/pneumonia in children remains unclear. We conducted a retrospective study involving 51 children (23 F, 29M, mean age 4,8 ± 2,9 y) with recurrent bronchitis/ pneumonia persisting despite correct symptomatic treatment. All children were evaluated between 2008 and 2013 for hiatus hernia by barium study of the upper gastro intestinal tract (BSUGT) and gastro-esophageal reflux by 24 hours pH metry (pHM). 80 % had normal pHM; 74,5% had transhiatal protrusion of gastric mucosa (15 mild, 23 moderate). 11 % had pathological pHM and protrusion; 17 % had no reflux and normal BSUGT. No correlation was found between frequency of bronchitis/pneumonia, acid reflux and transhiatal protrusion. The severity of protrusion was associated with vomiting (r=0,640, p=0,008); there was a trend for an association with wheezing (r=0,310, p=0,07). No correlation was found between the percentage of acid reflux, vomiting, wheezing, nocturnal or dry cough. All children with protrusion were treated with proton-pump inhibitors (PPI), as were the children with reflux. The frequency of bronchitis /pneumonia decreased after onset of treatment, and this benefit persisted after 11,7 ±2,8 months (6,7 ± 5,7/y before, vs 0,8 ±1,2/y after treatment, p We conclude that BSUGT is useful in investigating children with recurrent bronchitis/ pneumonia. The frequency of bronchitis/pneumonia in patients with transhiatal protrusion of gastric mucosa decreased after the onset of PPI, even in case of normal pHM.

BACKGROUND:Primary ciliary dyskinesia (PCD) is a rare disorder with variable disease progression. To date, mutations in more than 20 different genes have been found. At present, PCD subtypes are described according to the ultrastructural defect on transmission electron microscopy (TEM) of the motile cilia. PCD with normal ultrastructure (NU) is rarely reported because it requires additional testing. Biallelic mutations in DNAH11 have been described as one cause of PCD with NU.The aim of our study was to describe the clinical characteristics of a large population of patients with PCD, in relation to the ultrastructural defect. Additionally, we aimed to demonstrate the need for biopsy and cell culture to reliably diagnose PCD, especially the NU subtype.METHODS:We retrospectively analyzed data from 206 patients with PCD. We compared the clinical characteristics, lung function, microbiology and imaging results of 68 patients with PCD and NU to those of 90 patients with dynein deficiencies and 41 patients with central pair abnormalities. In addition, we aimed to demonstrate the robustness of the diagnosis of the NU subtype in cell culture by data from genetic analysis.RESULTS:PCD with NU comprised 33% (68/206) of all patients with PCD. Compared to other subtypes, patients with PCD and NU had a similar frequency of upper and lower respiratory tract problems, as well as similar lung function and imaging. With the currently widely applied approach, without cell culture, the diagnosis would have been missed in 16% (11/68) of patients with NU. Genetic analysis was performed in 29/68 patients with PCD and NU, and biallelic mutations were found in 79% (23/29) of tested patients.CONCLUSIONS:We reported on the clinical characteristics of a large population of patients with PCD and NU. We have shown that systematic performance of biopsy and cell culture increases sensitivity to detect PCD, especially the subtype with NU.PCD with NU has similar clinical characteristics as other PCD types and requires biopsy plus ciliogenesis in culture for optimal diagnostic yield.

Le syndrome de Prader-Willi (SPW) est une maladie neurogenetique complexe et rare caracterisee par une hypotonie neonatale severe, une hyperphagie et une obesite d’apparition precoce, une petite taille, un hypogonadisme et des troubles de l’apprentissage et du comportement. Le diagnostic, la prise en charge precoces et le traitement par GH ont transforme l’evolution de ces patients. Des reactions negatives a certains medicaments ou anesthesie, une insensibilite a la douleur, l’absence de vomissements, l’absence de temperature peuvent compliquer le diagnostic et la prise en charge de situations medicales urgentes Article Paru dans le numero special : Maladies rares : mieux les connaitre et les reconnaitre

Introduction: The presence of ultrastructural abnormalities (UA) on transmission electron microscopy (TEM) is proposed as gold standard for the diagnosis of Primary Ciliary Dyskinesia (PCD). Functional evaluation after ciliogenesis in culture (CC) is only proposed if the diagnosis is doubted. Because secondary changes are frequent, all samples are evaluated by CC at our centre. Since the detection of a DNAH11 mutation, the existence of the subtype normal ultrastructure but abnormal motility (NU) is proven. Using CC, we show that this subtype is not as rare as thought. Methods : Over 22 years, the CC procedure was used in 3077 subjects, of which 200 were diagnosed as PCD. Epithelial cells are isolated from nasal biopsies and cultured as a monolayer. After losing all the cilia they are brought into suspension, to gain cilia de novo . Results : UA was found in 133 subjects, NU in 67. In only 35 of the NU, ciliary beat frequency (CBF) could be measured before CC. It was abnormal in 22 and normal in 13, with absent ciliary coordination in 7 of these 13. After CC, all the samples lacked coordination, pathognomonic for PCD. CBF was abnormal in 50 and normal in 17 subjects. Repeat biopsy in 18 patients was identical. CC was the only technique to make the diagnosis of PCD in 39 subjects. nNO did not significantly differ from the UA group. There was familial occurrence of NU in 4 sibling pairs, consanguinity in 13.6%, situs inversus in 34%. The clinical characteristics (bronchiectasis, nasal secretions, hearing loss, draining ears, polyposis nasi, infertility) were similar in UA and NA. Conclusion : CC is the most reliable tool to diagnose PCD and unambigouosly detect patients with PCD and NA who might be missed when using other diagnostic methods.

Background : In Belgium in 2011, 35% of the 15-29 years age group were regular smokers. No information was available about epidemiology of smoking by CF patients in our country. Objectives : a) primary aim: to identify active (AS) and passive (PS) smokers in the Belgian CF patients b) secondary aim: to investigate physical, psychological and behavioural dependence of AS CF patients. Methods : AS and PS were identified by means of a urinary cotinine dosage. Patients with positive results were asked to meet with a tobacologist, in order to evaluate their expired CO, their physical, psychological and behavioral dependance to nicotine, and their HAD score. Results : (Interim analysis) 29 out 706 patients (4.5%, 78.8% of target) had positive urinary cotinine (> 100 mcg/ml); 17 positive patients met the tabacologist (12 AS, 5 PS). Among AS (mean age 28y ± 10, 84%M), mean urinary cotinine level was 0.863mcg/ml ± 0.464 (0.165 to1.5); mean exp CO was 13.3 ppm ± 7.6 (5-25); Fagestrom score was 4.5± 3 (1-9). 84% had a previous quit attempt. 41% AS smoked cannabis. Anxiety was associated with urinary cotinine level (R=0.825, p=0.009). All AS wished to receive specific help for smoking cessation at their CF reference center. Conclusions : Active smoking is less prevalent among CF patients in Belgium than in healthy adolescents and young adults. CF AS had developed a moderate physical dependance to nicotine; their urinary cotinine was associated with their anxiety level. Smoking cessation help should be available at CF reference centers.

En depit des progres considerables qu'il a permis, l'actuel traitement symptomatique de la mucoviscidose est trop lourd, trop cher et reste parfois clairement inefficace. Meme si n'en profiteront pleinement que les patients dont les poumons auront pu etre largement preserves jusqu'alors, il est necessaire de decouvrir un traitement plus fondamental de la maladie pulmonaire. La voie la plus prometteuse est aujourd'hui celle d'une approche pharmacologique taillee sur mesure en fonction des mutations de chaque patient. Elle vise a remedier en partie a leurs consequences sur la fonction de la proteine CFTR, deficiente dans cette affection. Ciblant au depart une mutation qui concerne moins de 0.5% des patients en Belgique, les deux premieres etudes de l'Ivacaftor sortent du lot. L'interet de cette medication - isolement ou en combinaison avec d'autres molecules - s'etend maintenant vers d'autres mutations. La tolerance mais aussi l'efficacite a long terme de cette substance restent cependant a evaluer. Tres eleve, son prix de vente actuel aux Etats-Unis pose question.

BACKGROUND:The diagnosis of intestinal malrotation is based on an upper gastrointestinal contrast series (UGI), which is considered the imaging reference standard. It may however be challenging even for experienced paediatric radiologists.OBJECTIVE:The purpose of this study was to demonstrate the agreement between UGI and US in assessing the position of the third portion of the duodenum (D3) and to show that a retroperitoneal duodenum indicates normal forgut rotation.MATERIALS AND METHODS:In a prospective study, US assessment of the duodenum and the superior mesenteric vessels was performed in consecutive children who were referred for clinically indicated UGI at a single institution.RESULTS:Eighty-five children, 5 months to 14 years old, were studied. In 82/85 (96%), both US and UGI suggested normal forgut rotation. In three children, US demonstrated a normal position of the D3 whereas UGI showed an abnormal position of the duodeno-jejunal junction.CONCLUSION:US is a non-invasive, easily performed technique for excluding malrotation. UGI may be reserved for situations where US does not demonstrate a normal position of the D3.

Le pronostic de la mucoviscidose est conditionne par l’atteinte pulmonaire. Trois types de facteurs l’influencent: des facteurs lies a la qualite de la prise en charge, des facteurs genetiques et des facteurs d’environnement. Les premiers sont les plus importants. Une prise en charge specialisee precoce est necessaire mais des differences considerables de resultats cliniques peuvent exister entre les centres. Mieux comprendre ces differences permettrait une amelioration globale du niveau des soins. Sous un autre angle, les implications pronostiques de ces differences sont telles que l’acces des patients et/ou parents a ces donnees est aujourd’hui considere aux USA comme un droit. Couple a une prise en charge optimale immediate, un depistage neonatal de la mucoviscidose devrait etre prochainement mis en place en Belgique et contribuer encore a l’amelioration du pronostic. L’etape decisive esperee est la decouverte d’un traitement plus fondamental de l’atteinte respiratoire. Une approche pharmacologique taillee sur mesure en fonction des mutations de chaque patient est la voie la plus prometteuse. En voie d’enregistrement aux USA, le compose VX-770 ne concernerait que quelques patients en Belgique mais pourrait bien constituer le premier traitement efficace de ce type. En attendant, le maintien de la solidarite dont ont besoin ces patients reste crucial.

Little is known about the onset and spontaneous progression and routine lung function testing is not available for monitoring of early CF lung disease.The aim of the present study was to validate pulmonary MRI as a radiation-free, non-invasive imaging modality to study the onset and progression of lung disease in infants and young children with CF.In 34 CF patients (age: 2.5±0.4;17 f, 17 m) MRI (1.5T) was performed in free breathing.For morphological imaging we used T2w-(HASTE PACE) and T1w T1-TSE sequences pre and post contrast media in coronal and transversal orientation.Functional measurements were performed with a 3D-FLASH-sequence with a temporal resolution of 1.5 s after iv injection of Gadolinium-DTPA.Two independent radiologists analyzed the images using a dedicated MRI score (range 0-72).Morphological and functional abnormalities in the CF lung were detected by MRI in the first year of life (MRI score 6.3±1.1;n = 6) and the score increased significantly to 16.2±1.7 (p < 0.05; n = 5) at the age of 4 years.Of note, perfusion defects preceded morphological abnormalities and were reversible in follow up scans in a substantial number of patients.Further, MRI scores were reduced after antibiotic therapy for pulmonary exacerbations (pre treatment: 20.2±7.7vspost treatment 13.0±4.9;p < 0.05).Our study indicates that MRI of the lung is sensitive to detect abnormal morphology, function and response to therapy in early CF lung disease.These results suggest that MRI may be suitable for non-invasive diagnostic monitoring of disease severity and may serve as a novel endpoint for clinical trials in early CF lung disease.Supported by Mukoviszidose e.V.

Background: Published studies concerning the impact of specialist care on lung disease in cystic fibrosis remain limited and most are either biased due to comparison with historical controls and/or underpowered.Methods: In this retrospective multicentric study, data from all CF children fulfilling the following criteria were collected: 1) Age 6-< 18 at the end of 2003; 2) diagnosis before 8 y; 3) follow-up in an accredited CF Belgian centre; 4) at least 1 spirometry and respiratory culture available for 2003. Group A included children referred >= 2 years after the diagnosis. Patients from Group A were then matched with a single early referred patient on the basis of 2 criteria: same centre, as closest age as possible (Group B).Results: Data from 217 children were collected (Group A: 67/217). Late referred patients had a lower FEV1 (77.2% +/- 22.4 vs 86.7% pred. +/- 19.4, p = 0.01) and a higher prevalence of Pseudomonas aeruginosa (38.6 vs 17.5%, p < 0.05).Conclusion: In this population of CF children, a delay of 6.1 y (vs 0.1 y) between diagnosis and referral to a specialist clinic resulted in poorer respiratory outcome at age 13. (c) 2008 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Nebulisers are a potential source of bacterial contamination in cystic fibrosis (CF) patients. The aims of the study were to survey patient practice regarding maintenance of home nebulisers and to assess the impact of standardised guidelines derived from a previous in-vitro study. In total, 42 CF patients were studied. During two consecutive home visits, a questionnaire regarding routine patient practice was completed by a nurse while sputum and equipment samples were taken for bacteriological analyses. The first visit took place at baseline, and the second followed the implementation of detailed instructions for cleaning and disinfecting the nebulisers using a 0.5% hypochlorite solution. The first visit identified a great diversity in routine patient practices. Commensal bacteria, environmental bacteria and potential CF pathogens contaminated 78.5%, 57.1% and 14.3% of nebulisers respectively. After hypochlorite disinfection, rate and degree of global contamination decreased significantly, but the number of CF pathogens was not affected. There was no concordance between CF pathogens isolated from patients' sputum and their equipment. We conclude that in this sample of patients, initial routine practices were varied. With regard to CF pathogens, the superiority of a hypochlorite solution over a mix of other disinfection methods was not demonstrated.