Research in progress: put the orphanage out of business.

Paediatric interstitial lung disease (ILD) is rare and diverse, meaning no single centre will see sufficient children to perform the studies needed to make progress. This EU FP-7 grant will standardise the evaluation of these rare conditions by establishing pan-European multidisciplinary expert panels and establish consensus on treatment protocols and standard operating procedures across Europe. We will work with patient groups to determine optimal treatment end-points and biomarkers. A biobank will be established as a Europe-wide resource for mechanistic studies. Ultimately we aim to do the first randomised controlled trial of a pharmacological treatment in paediatric ILD.

[Hereditary hemorrhagic telangiectasia]. / La maladie de Rendu-Osler (télangiectasie hémorragique héréditaire).

Hereditary hemorrhagic telangiectasia, also known as Rendu-Osler - Weber disease, is a rare, autosomal dominant vascular disease, with prevalence of 1/5,000. The condition is characterized by muco-cutaneous telangiectasias, which are responsible for a hemorrhagic syndrome of variable severity, as well as arteriovenous malformations (AVMs) appearing in the lungs, the liver, and the nervous system. They can be the source of shunts, which may be associated with high morbidity (neurological ischemic stroke, brain abscess, high-output heart failure, biliary ischemia…). It is therefore crucial to establish a clinical diagnosis using the Curaçao criteria or molecular diagnosis based on genetic analysis of the ENG, ACVRL1, SMAD4 and GDF2 genes. In most cases, multidisciplinary management allows patients to have normal life expectancy. Advances in interventional radiology and better understanding of the pathophysiology of angiogenesis have resulted in improved therapeutic management. Anti-angiogenic treatments, such as bevacizumab (BVZ, an anti-VEGF antibody), have proven to be effective in cases involving bleeding complications and severe liver damage with cardiac repercussions. Other anti-angiogenic agents are currently being investigated, including tyrosine kinase inhibitors.

New surfactant protein C gene mutations associated with diffuse lung disease.

BACKGROUND: Mutations in the surfactant protein C gene (SFTPC) have been recently associated with the development of diffuse lung disease, particularly sporadic and familial interstitial lung disease (ILD). OBJECTIVE: We have investigated the prevalence and the spectrum of SFTPC mutations in a large cohort of infants and children with diffuse lung disease and suspected with surfactant dysfunction. METHOD AND RESULTS: 121 children were first screened for the common SFTPC mutation, p.Ile73Thr (I73T). Ten unrelated patients were shown to carry this mutation. The I73T mutation was inherited in six cases, and appeared de novo in four. The 111 patients without the I73T mutation were screened for the entire coding sequence of SFTPC. Of these, eight (seven unrelated) subjects were shown to carry a novel mutant allele of SFTPC. All these seven new mutations are located in the BRICHOS domain except the p.Val39Ala (V39A) mutation, which is in the surfactant protein C (SP-C) mature peptide. CONCLUSIONS: Our results confirm that SFTPC mutations are a frequent cause of diffuse lung disease, and that I73T is the most frequent SFTPC mutation associated with diffuse lung disease.

[Antibiotic strategy in pleural empyema in children: Consensus by the DELPHI method]. / Stratégie antibiotique dans les pleurésies en pédiatrie : consensus par méthode DELPHI.

INTRODUCTION: The evolution of the microbial epidemiology of pleuropulmonary infections complicating community-acquired pneumonia has resulted in a change in empirical or targeted antibiotic therapy in children in the post Prevenar 13 era. The three main pathogens involved in pleural empyema in children are Streptococcus pneumoniae, Staphylococcus aureus and group A Streptococcus. METHODS: A questionnaire according to the DELPHI method was sent to experts in the field (paediatric pulmonologists and infectious disease specialists) in France with the purpose of reaching a consensus on the conservative antibiotic treatment of pleural empyema in children. Two rounds were completed as part of this DELPHI process. RESULTS: Our work has shown that in the absence of clinical signs of severity, the prescription of an intravenous monotherapy is consensual but there is no agreement on the choice of drug to use. A consensus was also reached on treatment adjustment based on the results of blood cultures, the non-systematic use of a combination therapy, the need for continued oral therapy and the lack of impact of pleural drainage on infection control. On the other hand, after the second round of DELPHI, there was no consensus on the duration of intravenous antibiotic therapy and on the treatment of severe pleural empyema, especially when caused by Staphylococci. CONCLUSIONS: The result of this work highlights the needed for new French recommendations based on the evolution of microbial epidemiology in the post PCV13 era.

Bacterial killing is enhanced by exogenous administration of lysozyme in the lungs.

OBJECTIVE: Lysozyme, a 14-kDa protein, is one of the most abundant antimicrobials in the lungs. Its concentration in airway surface sufficient to kill several bacterial pathogens in vitro. The purpose of this study was to determine if administration of exogenous lysozyme would further enhance bacterial killing in vivo. METHODS: To assess the effect of acute lung infection on endogenous lysozyme protein levels, mice were infected by intratracheal instillation of Pseudomonas aeruginosa and bronchoalveolar (BAL) fluid assessed for lysozyme concentration and for muramidase activity. In order to inform in vivo testing, species-specific bacterial killing efficacy was determined by incubating mucoid P. aeruginosa with 2×105 units of chicken lysozyme, human lysozyme or with vehicle at 37°C for 2hours. Subsequently, mice challenged with intratracheally-administered mucoid P. aeruginosa, were reintubated and injected with 2×105 Units of native human lysozyme, recombinant human lysozyme or with vehicle. Lung bacterial burden was enumerated subsequently. RESULTS: The concentration of lysozyme protein in BAL fluid from mice challenged with mucoid clinical isolate of P. aeruginosa was increased 4-fold at 6hours post-infection. Quantitative culture showed that the number of recoverable bacteria was significantly decreased by both chicken and human lysozyme compared to vehicle but human lysozyme was significantly more effective than chicken egg lysozyme. In vivo, 24hours post-infection quantitative culture of lung homogenates showed that the number of viable bacteria recovered from mice treated with either native or recombinant lysozyme was decreased with 0.76±0.25×104 and 0.84±0.16×104, respectively, vs. 7.0±2.52×104 CFU/g protein in mice treated with HBSS, both P<0.05. CONCLUSIONS: These results indicate that endogenous lysozyme is increased during acute lung infection and that early administration of exogenous lysozyme further enhances bacterial killing in vivo.

Protein-losing gastropathy associated with cytomegalovirus in two sisters - Case reports and review of the literature.

Ménétrier's disease is a protein-losing gastropathy that is uncommon in childhood. Its symptoms are unspecific, with abdominal pain, vomiting, and edema. Blood tests show hypoproteinemia and hypoalbuminemia, and upper digestive endoscopy reveals giant gastric folds. In children, cytomegalovirus has been identified as a possible cause. Here we describe two sisters presenting with Ménétrier's disease, 2 years apart. This diagnosis should be considered in the presence of hypoalbuminemia in children when a nephrotic syndrome is excluded.

[Early determinants of chronic obstructive pulmonary disease: Lung regeneration, a new therapeutic target?] / Déterminants précoces de la bronchopneumopathie chronique obstructive : la régénération pulmonaire, une nouvelle piste thérapeutique ?

Chronic obstructive pulmonary disease, a disease of increasing incidence, is related mainly to smoking. Although symptoms only appear at adulthood, the disease can develop from early life events. For example, bronchopulmonary dysplasia, which occurs in preterm infants, is characterized by airspace enlargement and could lead to late lung consequences. Once the lesions are established, no curative treatment is available. Stimulating lung regeneration from endogenous stem cells is therefore an exciting research domain, particularly through the activation of the mesenchymal contingent located in the lung stem cell niche.

[Lung diseases associated with inherited disorders of surfactant metabolism]. / Pathologies respiratoires associées à des anomalies héréditaires du métabolisme du surfactant.

Lung diseases associated with surfactant-metabolism disorders are a heterogeneous group of rare diseases. Intra-alveolar accumulation of protein related to surfactant dysfunction leads to cough, hypoxemia, and radiological-diffuse infiltration. Inherited deficiency of pulmonary surfactant protein B (SP-B) was initially described in infants who develop respiratory failure at birth. More recently, mutations in other constitutive surfactant proteins, such as surfactant protein C or implied in its metabolism, such as ATP-binding cassette, subfamily A, member 3 (ABCA3) and thyroid transcription factor 1 (TTF-1) were identified in newborns with respiratory distress as well as in children with chronic-infiltrative pneumonia. The aim of this review is therefore to summarize the current state of our knowledge in this area.

[Pneumocystis jiroveci pneumonia during prolonged corticosteroid therapy in an immunocompetent infant]. / Pneumonie àPneumocystis jiroveci au cours d'une corticothérapie prolongée chez un nourrisson immunocompétent.

INTRODUCTION: Pneumocystis jiroveci (PJ) infection is rare in infants and is suggestive of primary or secondary immunodeficiency. We report on a case of severe PJ pneumonia in an immunocompetent infant after prolonged corticosteroid treatment. CASE REPORT: A 5 1/2 month-old girl presented with hypoxemic respiratory distress. Her medical record was remarkable only for a bulky parotid haemangioma, which was treated with prolonged oral corticosteroid therapy. The chest X-ray showed a mixed alveolar-interstitial pattern, and bronchoalveolar lavage revealed the presence of PJ. A favourable outcome was obtained after three weeks of intravenous trimethoprim-sulfamethoxazole treatment. CONCLUSION: PJ infection should be suspected in infants presenting with progressive respiratory distress associated with a mixed alveolar-interstitial pattern. Its potential seriousness justifies prophylactic therapy during prolonged immunosuppressive treatment (chemotherapy, corticosteroid treatment).

Unusual long survival despite severe lung disease of a child with biallelic loss of function mutations in ABCA-3.

Homozygous or compound heterozygous for frameshift or nonsense mutations in the ATP-binding cassette transporter A3 (ABCA3) is associated with neonatal respiratory failure and death within the first year of life without lung transplantation. We report the case of a newborn baby girl who developed severe respiratory distress soon after birth. She was diagnosed with compound heterozygous frameshift mutation of the ABCA3 gene. Despite extensive treatment (intravenous corticosteroids pulse therapy, oral corticosteroids, azithromycin, and hydroxychloroquine), she developed chronic respiratory failure. As the parents refused cardio-pulmonary transplantation and couldn't resolve to an accompaniment of end of life, a tracheostomy was performed resulting in continuous mechanical ventilation. A neurodevelopmental delay and an overall muscular dystrophy were noted. At the age of 5 years, after 2 episodes of pneumothorax, the patient died from severe respiratory failure. To our knowledge, this was the first case of a child with compound heterozygous frameshift mutation who posed such an ethical dilemma with a patient surviving till the age of five years.

[Seasonality in asthma: Impact and treatments]. / La saisonnalité dans l'asthme : causes et approches thérapeutiques.

The role of seasons should be taken into account in the management of asthma. The environment varies between seasons and it is well documented that asthma is modulated by environment. Viruses cause asthma exacerbations peak, in winter, in adults while the peak is present in September in children. Allergens are probably a less powerful source of asthma exacerbation than viruses but pollen involvement in spring and summer and dust mites in autumn are indisputable. Air pollutants, present in summer during the hottest periods, are also highly involved in asthma exacerbations. Indoor air pollution, in winter, is also implicated in asthma disease. All these environmental factors are synergistic and increase the risk of asthma exacerbation. Therapies should be adapted to each season depending on environmental factors potentially involved in the asthma disease.

[Penicillin-resistant pneumococcal pneumonia (serotype p14), and coinfection with respiratory syncytial virus and Mycoplasma]. / Pleuro-pneumopathie à pneumocoque résistant à la pénicilline (sérotype p14), et co-infection à virus respiratoire syncytial et mycoplasme.

A 3-year old child was admitted for a pneumococcal pneumonia with pleural effusion, initially treated with amoxicillin and clavulanic acid. Clinical deterioration suggested a resistance to conventional antibiotics which was confirmed by bacteriological investigation. A co-infection with respiratory syncitial virus and Mycoplasma pneumoniae was associated. Under adapted antibiotherapy, the clinical course improved.

[Diseases of the pulmonary lymphatic system in children]. / Pathologies des lymphatiques pulmonaires chez l'enfant.

Diseases of the lymphatic system in children include a group of exceptional conditions difficult to manage. The anatomy of lymphatic system is complex in the lung. Variable from one subject to another, its complex physiology plays an important role in air-blood exchanges occurring in the lung. In the pulmonary interstitium and in the pleura, the lymphatic system acts like an overflow valve capable of regulating variations in interstitial fluid. The presence or development of dysplasic lymphatics causes leakage, dilatation, and reflux of the lymph through incontinent valves leading to chylothorax and/or fluid overload in the pulmonary interstitium. Symptomatic care is usually proposed, based on a fat-free diet supplemented with light-chain triglycerides and liposoluble vitamins. Other therapeutic options can be proposed. Medical options include cytotoxic agents, somatostatin, and interferon-alpha. Surgery may also be useful, but an assessment of therapeutic efficacy is very difficult due to partial effects and the small number of cases studied.

Sarcoidosis in children: HRCT findings and correlation with pulmonary function tests.

RATIONALE: High-resolution computed tomography (HRCT) plays an important role in the diagnosis and staging of pulmonary sarcoidosis, but implies radiation exposure. In this light, we aimed to describe HRCT findings as well as their relationship with pulmonary function tests (PFT) in children with pulmonary sarcoidosis. METHODS: In a retrospective study, 18 pediatric patients with sarcoidosis, including 12 with pulmonary abnormalities (PA group) and 6 without pulmonary abnormalities (APA group) were followed over a 16-year period. Relationships between HRCT scores and PFT were studied by non-parametric Spearman's test at diagnosis and by restricted maximum likelihood (REML) analysis during follow-up. RESULTS: Forty-three HRCT were scored. Twelve patients showed abnormal HRCT findings at diagnosis with multiple nodules or micronodules, while ground-glass opacities were seen in 11 patients. Ten patients exhibited pleural thickening or thickening of the fissure and 6 had interlobular septal thickening at diagnosis. No correlation between HRCT and forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1), forced expiratory flow during the mid-half of the FVC (FEF(25-75)) and specific dynamical compliance (SpecC(Ldyn)) was found at diagnosis. However, linear mixed models showed that changes in total HRCT scores over time were significantly associated with SpecC(Ldyn), FVC, and FEV1 modifications. CONCLUSION: Radiologic findings in children with pulmonary sarcoidosis were similar to those in adults. HRCT and PFT are both essential investigations at diagnosis; however, the correlation between HRCT pulmonary parenchymal findings and PFT over time suggests the possibility of reducing the number of HRCT during follow-up to decrease unnecessary radiation exposure.

[Lung diseases in children associated with inherited disorders of surfactant metabolism]. / Pathologies respiratoires de l'enfant associées à des anomalies héréditaires du métabolisme du surfactant.

Pulmonary surfactant is a unique mixture of lipids and specific proteins that reduces surface tension at the air-liquid interface, preventing collapse of the lung at the end of expiration. Recessive loss-of-function mutations of pulmonary surfactant protein B (SP-B) was initially described in infants who develop respiratory failure at birth. More recently, mutations in other constitutive surfactant proteins like surfactant protein C or implied in its metabolism like ATP-binding cassette, sub-family A, member 3 (ABCA3) or NK2 homeobox (NKX2-1) were identified in newborn with respiratory distress but also in children with diffuse infiltrative pneumonia. Intra-alveolar accumulation of protein related to surfactant dysfunction leads to cough, hypoxemia and radiological abnormalities including ground-glass opacities and lung cysts. The clinical and radiological features associated with these genetic disorders, along with their treatment and outcome, are reviewed.

Massive splenomegaly and pancytopenia reuealing sarcoidosis in a child.

Clinical presentation of sarcoidosis in children is very variable and dependant upon age. Herein, we report the first association of massive splenomegaly and pancytopenia as the revealing mode of sarcoidosis in an 8-year-old girl who, despite bone marrow involvement, had a remarkable good outcome following steroid therapy.