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Children with preschool wheezing represent a very heterogeneous population with wide variability regarding their clinical, inflammatory, obstructive, and/or remodeling patterns. We hypothesized that assessing bronchial remodeling would help clinicians to better characterize severe preschool wheezers.The main objective was to identify bronchial remodeling-based latent classes of severe preschool wheezers. Secondary objectives were to compare cross-sectional and longitudinal clinical and biological data between classes, and to assess the safety of bronchoscopy.This double-center prospective study (NCT02806466) included severe preschool wheezers (1-5 years old), requiring fiberoptic bronchoscopy. Bronchial remodeling parameters (i.e., epithelial integrity, reticular basement membrane (RBM) thickness, mucus gland, fibrosis and bronchial smooth muscle (BSM) areas, density of blood vessels, and RBM-BSM distance) were assessed and evaluated by Latent Class Analysis. An independent cohort of severe preschool wheezers (NCT04558671) was used to validate our results.Fiberoptic bronchoscopy procedures were well tolerated. A two-class model was identified: Class BR1 was characterized by increased RBM thickness, normalized BSM area, density of blood vessels, and decreased mucus gland area, fibrosis and RBM-BSM distance compared to Class BR2. No significant differences were found between classes in the year prior to fiberoptic bronchoscopy. By contrast, Class BR1 was associated with a shorter time to first exacerbation and an increased risk of both frequent (3) and severe exacerbations during the year following bronchoscopy in the two cohorts.Assessing bronchial remodeling identified severe preschool wheezers at risk of frequent and severe subsequent exacerbations with a favorable benefit to risk ratio.

The crisis of antibiotic resistance represents a global public health challenge, affecting particularly patients with respiratory infections. The use of (bacterio)phages for the treatment of bacterial infections (phage therapy) seems safe but its effectiveness has not yet been proven by controlled clinical trials. Nevertheless, phage therapy is regaining interest, encouraged by published cases treated successfully with personalized phage combinations as well as significant advances at a preclinical level. Standardized approaches in phage production and treatment administration, as well as future translational studies, are needed to improve our understanding and explore the potential of phage therapy.La crise de l’antibiorésistance représente un enjeu considérable en santé publique, touchant particulièrement les patients avec des infections respiratoires. L’utilisation des (bactério)phages pour le traitement des infections bactériennes semble sécuritaire mais son efficacité n’a pas encore été formellement démontrée dans des essais cliniques contrôlés. La phagothérapie regagne de l’intérêt comme traitement personnalisé pour les patients qui ne répondent pas aux traitements standards, comme en témoignent les multiples cas publiés ainsi que des découvertes significatives au niveau préclinique. Des approches standardisées concernant la production et l’administration des phages ainsi que des études translationnelles sont nécessaires afin d’améliorer notre compréhension et d’explorer le potentiel de la phagothérapie.

Resume Les dyskinesies ciliaires primitives (DCP) sont des maladies genetiques rares dues a des anomalies de structure et/ou de fonction des cils mobiles, responsables d’un defaut d’epuration muco-ciliaire. Ces dysfonctions ciliaires conduisent a des infections chroniques des voies aeriennes superieures et inferieures, de debut possiblement neonatal. L’evolution, de gravite variable, se fait vers une rhinosinusite chronique parfois invalidante et des bronchiectasies progressives, mais l’esperance de vie est consideree comme peu diminuee. Environ la moitie des patients presentent des anomalies de lateralisation des visceres pouvant alors s’inscrire dans la triade du syndrome de So (sinusite chronique, bronchiectasies, situs inversus). Une infertilite masculine est possible, par mobilite anormale du flagelle des spermatozoides dont la structure interne est tres proche de celle des cils mobiles. Le diagnostic repose sur la mesure du debit nasal de monoxyde d’azote et l’analyse de la fonction et de l’ultrastructure des cils respiratoires. La genetique des DCP est complexe du fait de l’heterogeneite des anomalies ciliaires et du grand nombre de genes impliques (45 genes impliques a ce jour). Les patients requierent un suivi multidisciplinaire regulier, clinique, microbiologique, fonctionnel et radiologique. La prise en charge au long court repose principalement sur le drainage nasal et bronchique quotidien et l’antibiotherapie, permettant de reduire la morbidite et de proteger le capital pulmonaire des enfants atteints de DCP.

Background Severe asthma (SA) in children is a complex, heterogeneous disease, associated with a considerable burden. However, factors influencing asthma severity are poorly described and may differ according to age. Objective To determine whether factors associated with asthma severity differ between preschoolers with severe recurrent wheeze (SRW) and school-age children with SA. Methods Data from the French multicenter prospective observational cohort of preschool (3-6 years) children with SRW and nonsevere recurrent wheeze (NSRW) and school-age (7-11 years) children with SA and nonsevere asthma (NSA) (Pediatric Cohort of Bronchial Obstruction and Asthma) were analyzed. Results A total of 131 preschool children (92 SRW and 49 NSRW) and 207 school-age children (92 SA and 115 NSA) were included. In both univariable and multivariable analysis, SRW was associated with second-hand smoke exposure (multivariable analysis: odds ratio [95% CI], 29.8 [3.57-3910]) and exposure to mold/dampness at home (multivariable analysis: odds ratio [95% CI], 4.22 [1.25-18.2]) compared with NSRW. At school-age, history of atopic dermatitis and food allergy was more frequent in children with SA than in those with NSA. Multivariable analysis confirmed that SA was associated with a history of food allergy (odds ratio [95% CI], 5.01 [2.23-11.9]). Conclusions Our data suggest that factors influencing asthma severity may differ according to age. In preschool children with SRW, second-hand smoke and exposure to mold are predominant, whereas associated allergic disorders are mainly involved in SA at school-age.

Background Diagnosis of primary ciliary dyskinesia (PCD) is challenging since there is no gold standard test. The European Respiratory (ERS) and American Thoracic (ATS) Societies developed evidence-based diagnostic guidelines with considerable differences. Objective We aimed to compare the algorithms published by the ERS and the ATS with each other and with our own PCD-UNIBE algorithm in a clinical setting. Our algorithm is similar to the ERS algorithm with additional immunofluorescence staining. Agreement (Cohen's κ) and concordance between the three algorithms were assessed in patients with suspicion of PCD referred to our diagnostic centre. Results In 46 out of 54 patients (85%) the final diagnosis was concordant between all three algorithms (30 PCD negative, 16 PCD positive). In eight patients (15%) PCD diagnosis differed between the algorithms. Five patients (9%) were diagnosed as PCD only by the ATS, one (2%) only by the ERS and PCD-UNIBE, one (2%) only by the ATS and PCD-UNIBE, and one (2%) only by the PCD-UNIBE algorithm. Agreement was substantial between the ERS and the ATS (κ=0.72, 95% CI 0.53–0.92) and the ATS and the PCD-UNIBE (κ=0.73, 95% CI 0.53–0.92) and almost perfect between the ERS and the PCD-UNIBE algorithms (κ=0.92, 95% CI 0.80–1.00). Conclusion The different diagnostic algorithms lead to a contradictory diagnosis in a considerable proportion of patients. Thus, an updated, internationally harmonised and standardised PCD diagnostic algorithm is needed to improve diagnostics for these discordant cases., There is no gold standard test for diagnosing PCD. The use of existing diagnostic algorithms leads to contradicting results in many patients (15% in this study). Thus, an updated and internationally harmonised diagnostic guideline is needed. https://bit.ly/2U19Vvq

Cystic Fibrosis is a genetic disorder resulting in the absence or dysfunction of the CFTR protein, a chloride channel present on the surface of epithelia, particularly respiratory. Until recently, treatments only concerned the consequences of the disease. But a new type of molecules called « modulators », is already available to some patients and targets the origin of the disease. « Modulators » are divided into « potentiators », which improve the transport of chloride by the CFTR protein, and « correctors », increasing the amount of CFTR proteins. An oral triple therapy combining a potentiator and two correctors has just been approved in the USA and will treat 85 % of patients. The clinical benefit of « modulators » is remarkable, and these drugs are revolutionizing the treatment of Cystic Fibrosis.La mucoviscidose est une maladie génétique entraînant une absence ou des dysfonctions de la protéine

BackgroundPrimary ciliary dyskinesia (PCD) is a rare genetic disorder resulting in abnormal ciliary motility/structure, extremely heterogeneous at genetic and ultrastructural levels. We aimed, in light of extensive genotyping, to identify specific and quantitative ciliary beating anomalies, according to the ultrastructural phenotype.MethodsWe prospectively included 75 patients with PCD exhibiting the main five ultrastructural phenotypes (n=15/group), screened all corresponding PCD genes and measured quantitative beating parameters by high-speed video-microscopy (HSV).ResultsSixty-eight (91%) patients carried biallelic mutations. Combined outer/inner dynein arms (ODA/IDA) defect induces total ciliary immotility, regardless of the gene involved. ODA defect induces a residual beating with dramatically low ciliary beat frequency (CBF) related to increased recovery stroke and pause durations, especially in case of DNAI1 mutations. IDA defect with microtubular disorganisation induces a low percentage of beating cilia with decreased beating angle and, in case of CCDC39 mutations, a relatively conserved mean CBF with a high maximal CBF. Central complex defect induces nearly normal beating parameters, regardless of the gene involved, and a gyrating motion in a minority of ciliated edges, especially in case of RSPH1 mutations. PCD with normal ultrastructure exhibits heterogeneous HSV values, but mostly an increased CBF with an extremely high maximal CBF.ConclusionQuantitative HSV analysis in PCD objectives beating anomalies associated with specific ciliary ultrastructures and genotypes. It represents a promising approach to guide the molecular analyses towards the best candidate gene(s) to be analysed or to assess the pathogenicity of the numerous sequence variants identified by next-generation-sequencing.

In Switzerland, about 13 % of pregnant women smoke, giving birth to more than 11'000 infants per year exposed to tobacco in utero. Although this proportion is stable since the 2000's, the users of nicotine with new devices (electronic cigarettes, inhaled heated tobacco, sniffed or chewed tobacco) are increasing. The literature is unanimous about deleterious effects of prenatal exposure to tobacco smoke on the fetus, with multiple short- and long-term consequences. Available data suggest that in utero exposure to e-cigarette could also expose the fetus to a similar profile of adverse effects. In this article, we review briefly the known epidemiological and mechanistic data on the short- and long-term effects of prenatal cigarette smoke and nicotine consumption.En Suisse, environ 13 % des femmes enceintes fument, donnant naissance à plus de 11 000 nourrissons par an exposés au tabac in utero. Si cette proportion est stable depuis les années 2000, celle des nouveaux modes de consommation du tabac et de la nicotine (cigarette électronique, inhalation de tabac chauffé, tabac à priser ou à sucer) est en augmentation. La littérature est unanime sur les effets délétères de l’exposition anténatale au tabac sur le fœtus, avec de multiples conséquences à court et à long terme. Les études disponibles à ce jour suggèrent que l’exposition in utero à l’e-cigarette expose à un profil similaire d’effets secondaires indésirables. Dans cet article, nous revoyons brièvement les données épidémiologiques et mécanistiques connues des effets à court et à long terme de la fumée de tabac et de la nicotine en anténatal.

Background: Necrotizing pneumonia (NP) is an increasing lung infection mostly associated with pleural empyema. Objectives: We aimed to compare children with empyema with and without concomitant NP, in terms of risk factors, management and outcome. Methods: We retrospectively included children hospitalized between 2005-2014 with empyema to whom a computed tomography was performed. We recorded patient characteristics, clinical, biological (blood and pleural fluid) and radiological findings, medical and surgical treatments, and clinical, radiological and functional follow-up. Results: 35 children with empyema were included, including 25 with a concomitant NP. Patients with or without NP were undistinguishable, in terms of characteristics, symptoms at admission or detected pathogens. Pleural leucocytes were significantly higher in the empyema group (p = 0.0002) as pleural LDH (p = 0.002), and pleural/blood LDH ratio (p = 0.0005). Medical and surgical managements were similar between both groups. Complications occurred in 1/10 children with empyema alone (pneumatocele) and 5/25 with concomitant NP (bronchopleural fistula (n = 3), lobectomy, pneumothorax). The hospital length of stay and delay for chest X-ray normalization were similar in both groups. Conclusion: Except for minor biological parameters, the presence of concomitant NP in case of empyema does not change the presentation, clinical features, management and outcome, suggesting that the presence of additional NP to empyema should not be managed differently. Therefore, in case of empyema with suspected concomitant NP, chest CT should probably be restricted to abnormal worsening or when mandatory for surgical treatment.

Cystic fibrosis (CF) is a genetic disease caused by a bi-allelic mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. When the diagnosis cannot be confirmed by a positive sweat test or/and the identification of two CF-causing variants, international guidelines recommend the use of CFTR functional assays. These tests assess whether CFTR activity is normal or diminished/absent through measurement of CFTR-mediated chloride secretion/absorption., CFTR functional assays are not only useful for diagnostic purposes but can also serve as a surrogate outcome for clinical trials of CFTR modulators, which are emerging therapeutic agents designed to correct the malfunctioning protein. In the near future they could also be used as precision-medicine techniques, to help guidance and optimisation of treatment., Until now, sweat testing has been the only CFTR functional assay available in Switzerland. Since 2020, the Centre Hospitalier Universitaire Vaudois (CHUV) at Lausanne and the Lucerne Children's Hospital perform nasal potential difference measurement. Moreover, The Ecole Poly-technique Federale de Lausanne (EPFL) established a reliable procedure to generate adult intestinal organoids, i.e., stem cell-derived in-vitro grown mini tissues, extracted from rectal biopsies, which can be used to assess CFTR function in vitro., This narrative review describes the most popular CFTR functional assays, as well as their indications, limitations and availability in Switzerland.

International audience; Primary ciliary dyskinesia (PCD) is an autosomal-recessive disease due to functional or ultra-structural defects of motile cilia. Affected individuals display recurrent respiratory-tract infections; most males are infertile as a result of sperm flagellar dysfunction. The great majority of the PCD-associated genes identified so far encode either components of dynein arms (DAs), which are multiprotein-ATPase complexes essential for ciliary motility, or proteins involved in DA assembly. To identify the molecular basis of a PCD phenotype characterized by central complex (CC) defects but normal DA structure, a phenotype found in ∼15% of cases, we performed whole-exome sequencing in a male individual with PCD and unexplained CC defects. This analysis, combined with whole-genome SNP genotyping, identified a homozygous mutation in DNAJB13 (c.833T>G), a gene encoding a HSP40 co-chaperone whose ortholog in the flagellated alga Chlamydomonas localizes to the radial spokes. In vitro studies showed that this missense substitution (p.Met278Arg), which involves a highly conserved residue of several HSP40 family members, leads to protein instability and triggers proteasomal degradation, a result confirmed by the absence of endogenous DNAJB13 in cilia and sperm from this individual. Subsequent DNAJB13 analyses identified another homozygous mutation in a second family; the study of DNAJB13 transcripts obtained from airway cells showed that this mutation (c.68+1G>C) results in a splicing defect consistent with a loss-of-function mutation. Overall, this study, which establishes mutations in DNAJB13 as a cause of PCD, unveils the key role played by DNAJB13 in the proper formation and function of ciliary and flagellar axonemes in humans.

Liver transplantation (LT) is associated with high post-operative morbidity, despite excellent survival rates. With this retrospective study, we report the incidence of early and late pulmonary complications (PC) after LT, identify modifiable risk factors for PC and analyzed the role of PC in post-operative ventilation duration and hospital length of stay. In a series of 79 children (0-16 years) with LT over a 12 years period, early (3 months post-LT) PC occurred in 68 patients (86%). Sixty-four percent (64%) developed early major complications such as pulmonary edema, atelectasis, or pleural effusion. Atelectasis requiring an intervention (P ≤ .02), pulmonary edema (P ≤ .02), or elevated PELD/MELD scores (P = .05) were associated with an increase in total ventilation duration and length of stay in the ICU. Risk factors for early PC included preoperative hypoxemia (P = .005), low serum albumin at LT admission (P = .003), or early rejection (P = .002). About 20% of patients experienced late PC of which 81% were infections. Risk factor assessment prior to LT may ultimately help reduce early PC thereby possibly minimizing post-operative morbidity and ICU length of stay.

International audience; Objectives To describe the characteristics of pediatric cases of eosinophilic granulomatosis with polyangiitis (EGPA), a systemic necrotizing vasculitis rarely diagnosed in children, retrieved from the French Reference Center for rare pediatric lung diseases and compared with adult cases included in the French Vasculitis Study Group cohort. Methods Results We collected information on pediatric EGPA disease presentation, management, and outcome. Cases met the Lanham criteria and/or American College of Rheumatology classification criteria. Fourteen cases of pediatric EGPA were included, from 1980 to 2012, with a median follow-up of 58.5 months. Median age at diagnosis was 12.3 years. All cases had respiratory involvement. The organ systems most frequently involved were the upper airway (85%), skin (71%), digestive tract (64%), and heart (57%). Neurological and renal involvement were rare. Four of the fourteen children were positive for ANCA (30.7%). During follow-up, three children required intensive care and one child died. The relapse rate was 64%. In comparison with an adult cohort, we found more ENT, heart, and digestive-tract involvement, and fewer neurological manifestations. In children, the delay between asthma onset and diagnosis was shorter, and biopsies showed fewer features of vasculitis. Conclusion This French cohort is the biggest pediatric EGPA series described to date, with a long follow-up period. The findings confirm that pediatric EGPA has specific clinical, radiological, and histological characteristics that differ from adult EGPA. Development of systemic symptoms, and consequently diagnosis, occur with a shorter delay in children, mainly during the eosinophilic phase and leading to a specific presentation.

BACKGROUND The influence of airway remodelling and inflammation in preschoolers with severe recurrent wheeze on asthma outcomes is poorly understood. OBJECTIVE To assess their association with asthma symptoms and lung function at school age. METHODS Preschoolers (38.4 months) initially investigated with bronchial biopsies were re-assessed for asthma symptoms and lung function at school age. RESULTS Thirty-six of 49 preschoolers (73.5%) were assessed at 10.9 years. Twenty-six (72.2%) had persistent asthma. Submucosal eosinophil counts were higher in children with severe exacerbations at school age than in those without (16/0.1 mm2 [11.2-30.4] vs 8/0.1 mm2 [2.4-17.6], P = .02), and correlated with the number of severe exacerbations (P = .04, r = .35). Submucosal neutrophil counts correlated with FEV1/FVC (P < .01, r = .47) and FEF25-75% predicted (P = .02, r = .43). Airway smooth muscle (ASM) area correlated with FEV1/FVC (P < .01, r = .51). Vessel numbers negatively correlated with FEV1% predicted and FEV1/FVC (P = .03, r = -.42; P = .04, r = -.41; respectively) and FEF25-75% predicted (P = .02, r = -.46). CONCLUSION Eosinophilic inflammation in preschoolers with severe recurrent wheeze might be predictive of future severe exacerbations, neutrophilia might be associated with better lung function. Changes in ASM and vascularity might affect lung function at school age.

Mucociliary clearance is one of the major lines of defense of the respiratory system. The mucus layer coating the pulmonary airways is moved along and out of the lung by the activity of motile cilia, thus expelling the particles trapped in it. Here we compare ex vivo measurements of a Newtonian flow induced by cilia beating (using micro-beads as tracers) and a mathematical model of this fluid flow, presented in greater detail in a second companion article. Samples of nasal epithelial cells placed in water are recorded by high-speed video-microscopy and ciliary beat pattern is inferred. Automatic tracking of micro-beads, used as markers of the flow generated by cilia motion, enables us also to assess the velocity profile as a function of the distance above the cilia. This profile is shown to be essentially parabolic. The obtained experimental data are used to feed a 2D mathematical and numerical model of the coupling between cilia, fluid, and micro-bead motion. From the model and the experimental measurements, the shear stress exerted by the cilia is deduced. Finally, this shear stress, which can easily be measured in the clinical setting, is proposed as a new index for characterizing the efficiency of ciliary beating., Author summary Mucociliary clearance is the first line of defense of the human pulmonary airways. Mucus transporting debris, particles, microorganisms and pollutants is carried away by the coordinated motion of cilia beating at the surface of the airway epithelium. We present here an experimental, mathematical and numerical study aiming at defining a global index for assessing the efficiency of this beating. We measure experimentally the ciliary beat frequency, ciliary beat amplitude, and metachronal wavelength on ciliated edges obtained from nasal brushing. Properties of fluid motion are simultaneously extracted from micro-bead tracking next to the ciliated edge. A mathematical and numerical model is developed to describe the fluid motion induced by the cilia tips considered as a moving wall. Experimental and numerical results show that the bead velocity is a parabolic function of the distance to the wall. It allows us to infer the shear stress exerted by the cilia on fluid from micro-bead tracking. This quantity is proposed as a universal index characterizing the beating efficiency, which can be extracted in the current clinical setting.

Introduction La crise d’asthme severe est une urgence vitale dont le traitement repose sur l’association de corticoides par voie generale et de bronchodilatateurs par voie inhalee. Quand les bronchodilatateurs sont inefficaces ou irrealisables par voie inhalee, leur utilisation par voie intraveineuse est envisageable. En France, le salbutamol intraveineux a une autorisation de mise sur le marche chez l’enfant a partir de 2 ans dans l’asthme aigu grave, mais sa place et ses modalites d’utilisation varient en fonction des recommandations existantes, ainsi qu’entre ces recommandations et la pratique clinique. Le salbutamol intraveineux reste donc un medicament dont les modalites d’utilisation sont controversees, notamment parce que les effets indesirables sont mal connus en nature et en frequence. Les etudes qui repertorient ces effets indesirables sont anciennes pour beaucoup d’entre elles, heterogenes quant aux posologies et aux modalites d’utilisation et rapportent des prevalences variant de 0 a 100 % pour l’ensemble des effets indesirables, et de 0 a 66 % pour les effets indesirables graves. L’objectif principal de cette etude etait d’estimer la prevalence des effets indesirables attendus du salbutamol intraveineux chez l’enfant, en conditions reelles d’utilisation. L’objectif secondaire etait de decrire ses modalites d’utilisation dans notre etablissement. Methodes Nous avons realise une etude prospective, observationnelle, monocentrique, incluant les patients hospitalises a l’hopital des Enfants du CHU de Toulouse traites par salbutamol intraveineux de novembre 2015 a octobre 2016. Resultats Nous avons inclus 45 patients âges de 1 a 13,9 ans. Tous les patients ont presente au moins un effet indesirable. Nous n’avons releve aucun effet indesirable grave. La pression arterielle baissait de facon significative sous salbutamol intraveineux. La frequence cardiaque augmentait de facon significative dans les premieres heures du traitement. Nous n’avons releve aucun trouble du rythme. Un patient a presente une hypokaliemie apparue sous traitement et 3 patients ont presente une hyperglycemie apparue sous traitement. Conclusion Le recours au salbutamol intraveineux est plus large en termes d’indication et de posologies dans notre etablissement que ne le preconisent les recommandations existantes et l’autorisation de mise sur le marche francaise, cependant, nous n’avons pas mis en evidence d’effets indesirables graves malgre des effets indesirables non graves systematiques.

High speed videomicroscopy (HSV) becomes a key test in primary ciliary dyskinesia (PCD), providing a qualitative evaluation and recently a quantitative analysis of ciliary beating. We aimed to correlate ultrastructural phenotype and ciliary beating Method: 75 PCD patients were prospectively included to reach 15 patients per main ultrastructural phenotypes (combined outer/inner dynein arm defect, outer dynein arm defect, inner dynein arm defect with microtubular disorganization, central complex defect and PCD with normal ultrastructure). Ciliary beating was assessed by the proportion of beating ciliated edges, the ciliary beat frequency (CBF), a qualitative evaluation and a quantitative analysis allowing measuring objective parameters Result: Combined outer/inner dynein arm defect induced a total ciliary immotility, whatever the involved gene; (ii) Outer dynein arm defect induced a minimal residual beating with dramatically low CBF related to increased pause and recovery duration, especially in case of DNAI1 mutations; (iii) Inner dynein arm defect induced a weak proportion of ciliated edges still beating, a decreased beating angle and furthermore a relatively conserved CBF in case of CCDC39 mutations; (iv) Central complex defect induced nearly normal quantitative parameters with a circular gyrating motion in a minority of ciliated edges, whatever the involved gene; (v) PCD with normal ultrastructure induced a wide discrepancy in beating parameters but a frequent increased CBF Conclusion: Quantitative analysis by HSV allows objectively detecting abnormal values of ciliary beating parameters characteristic of each of the main ultrastructural phenotypes reported in PCD.

Background and Objectives Functional and structural lung evaluations are part of the follow-up of patients with primary ciliary dyskinesia (PCD). We aimed to evaluate transversal and longitudinal relationships between lung function test (LFT) and chest computed tomography (CT) in children with PCD, in stable clinical condition. Materials and Methods Data from children followed in the French National Center were retrospectively collected. Inclusion criteria were (i) definitive diagnosis of PCD, (ii) age less than 15 years at the beginning of follow-up, (iii) at least 8 years of follow-up, (iv) at least two couples of concurrent CT and LFT available in a phase of clinical stability of the lung disease without modification of the treatment regimen in the last 4 weeks. Twenty children (median age at entry 4.6 years, median follow-up 15.4 years) were included. Concurrent LFT (blood gas and spirometry) and CT (score) results were recorded. Results LFT indices (PaO2 (n = 210), FVC, FEV1, FEF2575% (n = 195)) significantly decreased with age, and the mean annual decrease (z-score (% predicted)) was −0.17 (−0.49%), −0.09 (−0.50%), −0.10 (−0.89%), and −0.07 (−1.73%), respectively. First CT (median age 8.7 years) revealed bronchiectasis (70%), mucous plugging (70%), peribronchial thickening (90%), parenchymal abnormalities (65%), and hyperinflation (50%). CT scores (n = 74) significantly increased with age, and was negatively correlated to PaO2, FVC, FEV1, and FEF2575% longitudinal changes. Conclusion In stable clinical condition, functional, and structural progressive impairments significantly correlated in children with PCD. Further prospective studies, including large populations of patients with various levels of disease severity, are needed to confirm whether lung function follow-up can be used to adjust CT frequency and help at minimizing the radiation burden in children with a good life expectancy. Pediatr Pulmonol. 2012. 47:816–825. © 2012 Wiley Periodicals, Inc.

Introduction Les infections fongiques a Rhizopus arrhizus sont opportunistes et invasives, touchant principalement les patients immunodeprimes ou en acidocetose. Observation Nous rapportons le cas d’une patiente de 15 ans, diabetique, presentant un syndrome cardinal apres l’arret de son insulinotherapie, avec acidocetose et dyspnee febrile. Le diabete est rapidement controle, mais elle est hospitalisee en reanimation pour pneumonie basale gauche et traitee par anti-infectieux probabilistes (amoxicilline-acide clavulanique/spiramycine/oseltamivir, puis piperacilline-tazobactam/linezolide. Les prelevements microbiologiques reviennent initialement negatifs, mais devant la mauvaise evolution clinique, radiologique et biologique, une recherche mycologique sur expectorations est realisee, retrouvant des filaments de Rhizopus arrhizus . Les scanners cerebral et sinusien sont normaux. La fibroscopie bronchique montre des membranes blanchâtres avec une muqueuse tres remaniee. Le lavage broncho-alveolaire, les biopsies muqueuses et les PCR sanguines sont positifs a Rhizopus arrhizus. Elle est initialement traitee par amphotericine B intraveineuse a forte dose (7,5 mg/kg/j). L’evolution est defavorable a 10 jours, avec un epanchement pleural necessitant un drainage, majoration des lesions pulmonaires gauches et apparition de lesions controlaterales. Le traitement est elargi par du posaconazole et caspofungine fortes doses et finalement pneumectomie gauche a 16 jours du debut de la prise en charge. Les PCR se negativent 4 jours apres la chirurgie permettant une desescalade therapeutique a 11 jours de la premiere PCR negative, puis une monotherapie par posaconazole pour une duree totale de 6 mois. Apres 6 mois de traitement: la patiente se plaint uniquement d’une dyspnee a l’effort, le scanner thoracique ne temoigne d’aucune lesion parenchymateuse, les EFR montrent une CV a 1,71L soit 58 % de la theorique. Discussion Ce cas clinique illustre la difficulte diagnostique et therapeutique de ces infections fongiques invasives. Les donnees de la litterature concernant les mucormycoses pulmonaires montrent des taux de mortalite de 50 a 80 % [1] , [2] . Les facteurs pronostiques sont la precocite du diagnostic et du traitement antifongique, la correction des facteurs favorisants (immunosuppression, equilibre du diabete…). Conclusion Il convient de multiplier les prelevements microbiologiques, notamment fongiques, dans les pneumonies resistantes aux antibiotiques, en particulier chez les patients a risque (immunodeprimes, diabete mal equilibre).

Resume Introduction L’infection a Pneumocystis jiroveci (PJ) est rare chez le nourrisson et fortement evocatrice de deficit immunitaire. Ce deficit immunitaire peut etre primitif ou secondaire. Nous rapportons un cas de pneumonie a PJ survenu chez une enfant au decours d’une corticotherapie prolongee. Observations Un nourrisson de 5,5 mois est hospitalise pour une detresse respiratoire hypoxemiante. Il ne presente aucun antecedent en dehors d’un volumineux hemangiome parotidien traite par une corticotherapie orale prolongee. La radio du thorax montre un syndrome alveolo-interstitiel et le lavage broncho-alveolaire confirme la presence de PJ. L’evolution est favorable apres trois semaines de traitement intraveineux par trimethoprime-sulfamethoxazole. Conclusion La pneumocystose doit etre systematiquement recherchee chez un nourrisson presentant une pathologie alveolo-interstitielle severe d’installation rapidement progressive. Sa gravite justifie la mise en place d’une chimioprophylaxie lors de tout traitement immunosuppresseur (chimiotherapie, corticotherapie prolongee).

We report a case of a 13-year-old girl with an asymptomatic isoniazid-resistant tuberculosis contact. Six months after the contact had been made, chest radiography showed left upper lobe infiltrates without hilar lymphadenopathy, which led to the start of an antituberculous treatment. Tuberculin skin test remained negative and blood tests showed hypereosinophilia. One month after the onset of the treatment, she presented with asthenia, weight loss, and cough. She was admitted to our unit with a diagnosis of drug-resistant tuberculosis. Blood tests showed the persistence of hypereosinophilia. Chest radiograph and high-resolution lung computed tomography (CT) scan showed alveolar peripheral condensations on both upper lobes without significant hilar lymphadenopathy. Bronchoalveolar lavage (BAL) showed a normal total cell count with 44% of eosinophils. Microbiological analyses were all negative. Chronic eosinophilic pneumonia (CEP) was confirmed after the elimination of other different eosinophilic lung diseases. The patient was highly responsive to high doses of oral corticosteroids. Dyspnoea and cough disappeared within one week and chest CT scan showed regression of the lung infiltrates within one month. No relapse occurred during the following nine months.

Objectif Paecilomyces lilacinus (PL) et variotii (PV) sont des champignons opportunistes emergents, non etudies dans la mucoviscidose. Methode Etude retrospective aux CRCM enfants et adultes de Toulouse sur les donnees informatisees du 01/01/2008 au 01/09/2014. Sont etudiees les caracteristiques des patients au 1 er isolement de Paecilomyces (P) dans l’expectoration, et leur evolutivite : VEMS et IMC en % de la norme, a 1 an et 2 ans avant et apres, et le type de colonisation bronchique chronique, intermittente ou ponctuelle. Resultat Sur cette periode sont realisees 3337 analyses microbiologiques de l’expectoration chez 98 enfants (de plus de 5 ans) et 164 adultes ; 39 (1,1 %) sont positifs pour P. Vingt patients ont au moins une fois du P : 2 colonisations chroniques (PL), 4 intermittentes (PL) et 14 ponctuelles (12 PL, 2 PV). Au 1 er isolement, l’âge median est de 13 ans (9 a 36), le VEMS median de 82 % (28 a 112) et le BMI median de 94 % (79 a 113). Tous sont colonises a Pseudomonas aeruginosa , 17 a S. aureus , et 14 a Aspergillus . La charge therapeutique semble elevee : l’annee precedente, 11 (55 %) ont de l’itraconazole, 13 une corticotherapie (12 inhalees, 1 par voie orale), 14 de l’azithromycine, 10 une antibiotherapie inhalee, 10 des ATB IV. Le profil des patients selon le type de colonisation ne differe pas, hormis l’itraconazole prescrit chez 100 % des patients chroniques et intermittents (vs 35 % chez les colonises ponctuels). P ne semble pas influencer l’evolutivite : VEMS et BMI restent stables. Conclusion P semble peu pathogene, mais survient chez des patients avec une charge therapeutique elevee. La sensibilite diminuee de P a l’itraconazole peut evoquer une pression de selection par ce traitement.

But Evaluer l’impact du depistage neonatal de la mucoviscidose sur l’evolution nutritionnelle precoce. Methode Etude retrospective monocentrique realisee du 1/10/02 au 31/12/12 qui a evalue au moment du diagnostic et vers un an les parametres nutritionnels cliniques et biologiques. L’analyse a ete faite en 3 sous-groupes en fonction de la valeur de l’elastase fecale initiale : suffisant (SP), intermediaire et insuffisant pancreatique (IP), respectivement elastase > 200, 15–200 et t de Student non apparie pour les variables continues, exprimees en moyenne ± DS, et en un test de Chi 2 pour les variables categorielles, exprimees en pourcentage. Resultats Cinquante-deux enfants ont ete diagnostiques durant cette periode dont 43 par depistage neonatal (7 pathologies chirurgicales neonatales et 2 faux negatifs). Ils etaient repartis en 8 SP (17 %), 10 intermediaires (21 %) et 28 IP (59 %). Lors de l’annonce, a 37 ± 14 jours, le poids etait significativement plus bas dans le groupe IP (−1,13 ± 1,18 DS, p p Au niveau biologique, les valeurs au diagnostic de l’albumine et du zinc serique etaient plus basses dans le groupe IP. Au cours du suivi, a ete notee une augmentation des taux d’acide eicosapentaenoique et une diminution du taux d’acide docosahexaenoique quel que soit le statut pancreatique. Concernant les vitamines liposolubles, la principale difference concernait la vitamine E dont le taux etait significativement plus bas au diagnostic dans le groupe IP vs. SP, respectivement de 5,8 ± 4,2 vs. 11,1 ± 3,4 mg/L ( p = 0,01). Conclusion Le depistage neonatal de la mucoviscidose a permis une correction a un an des anomalies nutritionnelles presentes au moment du diagnostic. Toutefois, une attention particuliere doit etre portee aux nourrissons ayant une fonction pancreatique « intermediaire », dont le statut nutritionnel a un an etait moins bon.

Plusieurs etudes ont mis en evidence que les mucormycoses connaissent une incidence croissante. Leur morbi-mortalite significative est connue chez les adultes mais il existe a ce jour peu de donnees en pediatrie. Ces infections, causees par les champignons filamenteux de l’ordre des mucorales, sont caracterisees par leur tendance a une invasion vasculaire rapide. Des atteintes localisees peuvent rapidement progresser vers les tissus mous, rhinocerebraux, orbitaires, gastro-intestinaux ou pulmonaires. Nous rapportons un cas de mucormycose invasive survenu chez une adolescente de 15 ans atteinte d’un diabete insulinodependant admise aux urgences pediatriques du CHU de Toulouse pour une decompensation acidocetosique accompagnee d’une pneumopathie bilaterale evoquant une infection virale surinfectee. Au 10 e jour, apres une phase d’amelioration et de sortie de reanimation, une infection fongique est evoquee devant une condensation lobaire inferieure gauche, une re-ascension de son syndrome inflammatoire et une aggravation de son etat general en depit d’une antibiotherapie probabiliste menee de facon optimale. L’expectoration induite, au 12 e jour d’hospitalisation, permet de mettre en evidence a l’examen direct des filaments de mucorales, confirmes a j14 sur le LBA et les biopsies bronchiques. Le traitement antifongique par Ambisome ® 7,5 mg/kg est immediatement debute. Les cultures fongiques sont restees steriles. Une PCR ciblant les mucorales (realisee sur les prelevements pulmonaires et le serum) et le sequencage nucleotidique ont permis de confirmer l’espece Rhizopus arrhizus . Compte tenu de la persistance de la positivite de la PCR serique et de l’aggravation endoscopique et tomodensitometrique, il est associe au 11eme jour de traitement du posaconazole et de la Caspofungine. Au 17 e jour une pneumonectomie gauche de sauvegarde est realisee dans des conditions difficiles. Depuis, l’etat de la patiente est en constante amelioration. Les PCRs fongiques se sont negativees tres rapidement apres l’intervention chirurgicale. En conclusion, les techniques moleculaires permettent une amelioration considerable du diagnostic biologique des mucormycoses. Devant la severite de ces infections, bien que rares, elles devraient etre recherchees de facon systematique chez d’adolescent diabetique se presentant pour une symptomatologie infectieuse pulmonaire lors d’une acidocetose afin d’instaurer un traitement optimal precocement.

Introduction Les dyskinesies ciliaires primitives (DCP) sont un groupe de maladies genetiques rares responsable d’une anomalie du mouvement des cils respiratoires. Le diagnostic est classiquement confirme grâce a l’identification d’une anomalie de l’ultra-structure ciliaire par microscopie electronique a transmission. L’analyse genetique ne peut etre proposee en premiere intention, etant donne le nombre (> 30 genes) et la taille (> 80 exons) des genes impliques. Nous avons souhaite etudier si la mesure objective du mouvement ciliaire par video-microscopie a haute vitesse pourrait predire le phenotype ultra-structural et ainsi guider l’analyse genetique. Methodes Nous avons prospectivement inclus 75 patients ayant un diagnostic certain de DCP, presentant un des 5 principaux phenotypes ultra-structuraux identifie par microscopie electronique (15 patients par groupe), et pour lesquels tous les genes correspondants ont ete sequences. L’etude du mouvement ciliaire a inclus le pourcentage de cil battant, la frequence de battement ciliaire, une evaluation qualitative et la mesure quantitative de 12 parametres du mouvement ciliaire. Resultats L’absence combinee des bras de dyneine externe et interne induit une immobilite ciliaire totale, quel que soit le gene implique. L’absence de bras de dyneine externe permet un rare mouvement ciliaire residuel avec une frequence de battement effondre en rapport avec un allongement du temps de pause, notamment en cas de mutation de DNAH1. L’absence de bras de dyneine interne avec desorganisation axonemale induit un faible pourcentage de cil battant avec une diminution de l’angle de battement, associe en cas de mutation de CCDC39 a une frequence maximale de battement augmentee. L’absence de complexe central permet un mouvement ciliaire relativement conserve, malgre une minorite de cil presentant un mouvement ciliaire circulaire, quel que soit le gene implique. Dans les DCP avec ultra-structure normale, les parametres de mouvement ciliaires ont des valeurs particulierement heterogenes, malgre une frequence de battement ciliaire augmentee avec une frequence maximale extreme. Conclusion L’analyse quantitative du mouvement ciliaire par video-microscopie a haute vitesse permet l’identification de parametres objectifs caracteristiques du phenotype ultra-structural des DCP.

International audience; Primary ciliary dyskinesia (PCD) is an inherited disease related to ciliary dysfunction, with heterogeneity in clinical presentation and in ciliary ultrastructural defect. Our study intended to determine if there are phenotypic differences in patients with PCD based on ciliary ultrastructural abnormality. In this retrospective study carried out among 60 children with a definitive diagnosis of PCD, we analyzed clinical, radiological, and functional features at diagnosis and at last recorded visit, according to cilia defect (absence of dynein arms: DAD group, n = 36; abnormalities of the central complex: CCA group, n = 24). Onset of respiratory symptoms occurred later in the CCA than in the DAD group (9.5 versus 0.5 months, p = 0.03). Situs inversus was only observed in the DAD group, while respiratory disease in siblings were more frequent in the CCA group (p = 0.003). At diagnosis, clinical presentation was more severe in the CCA group: frequency of respiratory tract infections (p = 0.008), rhinosinusitis (p = 0.02), otitis complications (p = 0.0001), bilateral bronchiectasis (p = 0.04), and number of hypoxemic patients (p = 0.03). Pulmonary function remained stable in both groups, but outcome was better in the CCA than in the DAD group: less antibiotic therapy and hypoxemic patients (p = 0.004). In conclusion, our results underlined the relationship between the severity of clinical presentation and the ultrastructural ciliary defect.

Background Primary Ciliary Dyskinesia (PCD) is a inherited disorder characterized by abnormal ciliary structure/function, responsible for impaired muco-ciliary transport and infertility. The diagnosis is often delayed for several years though PCD is a rare (~1/20,000) and heterogeneous disease. We elaborated recommendations aiming at improving the quality and efficacy of PCD diagnosis. Methods A multicentric working group, created in 2009 within the French National Centre for Rare Respiratory Diseases, elaborated precise and practical algorithm for PCD diagnosis, based on their experience and the recent literature. It includes adults and paediatric physicians, biologists and technicians involved in PCD, dealing since many years with the difficulties to confirm this diagnosis.

Background Primary Ciliary Dyskinesia (PCD) is a rare inherited disease (~1/20,000), characterized by ciliary structure/function abnormalities, responsible for impaired muco-ciliary transport, leading to recurrent upper and lower airways infections early in life and infertility. The diagnosis is confirmed on ciliate cell samples, collected by nasal and/or bronchial endoscopy. Patients usually need several samples, due to difficulties to get reliable results, especially during respiratory tract infections which are frequent in PCD. We created national guidelines aimed at obtaining the more efficient quality of ciliate cell samples for children and adults.

International audience; Background: CCDC39 and CCDC40 genes have recently been implicated in primary ciliary dyskinesia (PCD) with inner dynein arm (IDA) defects and axonemal disorganisation; their contribution to the disease is, however, unknown. Aiming to delineate the CCDC39/CCDC40 mutation spectrum and associated phenotypes, this study screened a large cohort of patients with IDA defects, in whom clinical and ciliary phenotypes were accurately described.Methods: All CCDC39 and CCDC40 exons and intronic boundaries were sequenced in 43 patients from 40 unrelated families. The study recorded and compared clinical features (sex, origin, consanguinity, laterality defects, ages at first symptoms and at phenotype evaluation, neonatal respiratory distress, airway infections, nasal polyposis, otitis media, bronchiectasis, infertility), ciliary beat frequency, and quantitative ultrastructural analyses of cilia and sperm flagella.Results: Biallelic CCDC39 or CCDC40 mutations were identified in 30/34 (88.2%) unrelated families with IDA defects associated with axonemal disorganisation (22 and eight families, respectively). Fourteen of the 28 identified mutations are novel. No mutation was found in the six families with isolated IDA defects. Patients with identified mutations shared a similar phenotype, in terms of both clinical features and ciliary structure and function. The sperm flagellar ultrastructure, analysed in 4/7 infertile males, showed evidence of abnormalities similar to the ciliary ones.Conclusions: CCDC39 and CCDC40 mutations represent the major cause of PCD with IDA defects and axonemal disorganisation. Patients carrying CCDC39 or CCDC40 mutations are phenotypically indistinguishable. CCDC39 and CCDC40 analyses in selected patients ensure mutations are found with high probability, even if clinical or ciliary phenotypes cannot prioritise one analysis over the other.

Background CCDC39 and CCDC40 genes have recently been implicated in primary ciliary dyskinesia (PCD) with inner dynein arm (IDA) defects and axonemal disorganisation; their contribution to the disease is, however, unknown. Aiming to delineate the CCDC39/CCDC40 mutation spectrum and associated phenotypes, this study screened a large cohort of patients with IDA defects, in whom clinical and ciliary phenotypes were accurately described. Methods All CCDC39 and CCDC40 exons and intronic boundaries were sequenced in 43 patients from 40 unrelated families. The study recorded and compared clinical features (sex, origin, consanguinity, laterality defects, ages at first symptoms and at phenotype evaluation, neonatal respiratory distress, airway infections, nasal polyposis, otitis media, bronchiectasis, infertility), ciliary beat frequency, and quantitative ultrastructural analyses of cilia and sperm flagella. Results Biallelic CCDC39 or CCDC40 mutations were identified in 30/34 (88.2%) unrelated families with IDA defects associated with axonemal disorganisation (22 and eight families, respectively). Fourteen of the 28 identified mutations are novel. No mutation was found in the six families with isolated IDA defects. Patients with identified mutations shared a similar phenotype, in terms of both clinical features and ciliary structure and function. The sperm flagellar ultrastructure, analysed in 4/7 infertile males, showed evidence of abnormalities similar to the ciliary ones. Conclusions CCDC39 and CCDC40 mutations represent the major cause of PCD with IDA defects and axonemal disorganisation. Patients carrying CCDC39 or CCDC40 mutations are phenotypically indistinguishable. CCDC39 and CCDC40 analyses in selected patients ensure mutations are found with high probability, even if clinical or ciliary phenotypes cannot prioritise one analysis over the other.

Methods Ciliated cells issued from nasal brushing (controls and primary ciliary dyskinesia patients) were recorded by high-speed video-microscopy (350 frames s). We have performed an original quantitative analysis of ciliary beat dynamics (CBD) by following cilium tips. It allows to describe different parameters including ciliary beat frequency also measured by Fast-Fourier-Transform and Video-Kymography. We have also developed the microbeads tracking method (MBT) to get an index of the global efficiency of ciliary beat. Here, micro-beads (4.5 μm) have been used as markers of the flow generated by beating cilia.