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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.

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.

Abstract Background Prenatal and early-life air pollution exposures have shown to play an important role in childhood respiratory and allergic diseases development. Our aim was to assess the effect of prenatal exposure to air pollution on several respiratory outcomes up to 12 years old. Methods We included 2054 children from the PELAGIE mother-child cohort in Brittany, France, followed-up at 2-, 6- or 12-years. Parents reported children's respiratory health history, family lifestyle and children immediate environment. PM2.5 and NO2 mean concentrations throughout the pregnancy were modelled at residential address using land use regression models. Ever asthma, rhinitis, allergic rhinitis and eczema at 12-years follow-up, considered as outcomes of interest, were defined using validated questionnaires. A multimorbidity phenotype was also constructed. We performed adjusted logistic regressions per increase of one interquartile range (IQR). Results Participating mothers’ mean age was 30 years (SD 4.1), 88% did not smoke during pregnancy, and 82% lived in rural areas. Fifty percent of children were boys; 55% of them had parents with history of asthma and/or allergies. Pregnancy concentrations of NO2 were 18.74±7.72μg/m3 (IQR=9.66) and PM2.5 15.11±2.21μg/m3 (IQR=3.38). Prevalence of asthma, rhinitis, allergic rhinitis and eczema was 28%, 11% and 38% respectively at 12-years follow-up. Overall, no significant associations were found with asthma, rhinitis or eczema, nor with the multimorbidity phenotype. Discussion/conclusions Prenatal exposures to ambient PM2.5 and NO2, at relatively low concentrations, did not show any significant associations with children's respiratory and allergic outcomes. Further analysis including logistic models stratified by sex and urban-rural area, and clustering approaches will be performed to assess if specific profiles of environmental exposures during pregnancy and early childhood are associated with childhood respiratory and allergic diseases. Key messages • The prenatal and postnatal periods are major vulnerability windows for children's respiratory health. • An exposome approach provides a better understanding of a larger set of urban/rural exposures and their associations with childhood respiratory and allergic diseases.

The aim of this work was to evaluate the effect of a more conservative use of chest-tube insertion on the short-term and long-term outcome of pleural infection. Sixty-five patients with pleural infection, aged 1 month to 16 years were each treated according to one of the two protocols: classical management with chest-tube insertion (classical group, n = 33), or conservative use of chest-tube insertion (conservative group, n = 32), with drainage indicated only in the case of voluminous pleural effusion defined by a mediastinal shift and respiratory distress and/or an uncontrolled septic situation. The two groups were comparable with regard to age, baseline C-reactive protein (CRP) value and white blood cell counts, pleural thickness, identified bacteria, and antibiotic treatment. Chest-tube insertion was performed in 17 patients (52%) of the classical group compared to eight patients (25%) of the conservative group (P = 0.03). Duration of temperature above 39 degrees C was shorter in the conservative group (10 +/- 1 vs. 14 +/- 1 days, P = 0.01), as was the normalization of CRP (13 +/- 1 vs. 17 +/- 1 days, P = 0.03). Duration of hospitalization and intravenous (IV) antibiotherapy as well as the delay of chest-radiograph normalization was not significantly different between the two groups. A more conservative use of chest-tube insertion did not change short- and long-term outcome of the pleural infection in children. Drainage could be restricted to the most severely affected patients with pleural empyema causing a mediastinal shift and respiratory distress and/or presenting with an uncontrolled septic situation.

Acute bronchiolitis treatment in children and infants is largely supportive, but chest physiotherapy is routinely performed in some countries. In France, national guidelines recommend a specific type of physiotherapy combining the increased exhalation technique (IET) and assisted cough (AC). Our objective was to evaluate the efficacy of chest physiotherapy (IET + AC) in previously healthy infants hospitalized for a first episode of acute bronchiolitis. We conducted a multicenter, randomized, outcome assessor-blind and parent-blind trial in seven French pediatric departments. We recruited 496 infants hospitalized for first-episode acute bronchiolitis between October 2004 and January 2008. Patients were randomly allocated to receive from physiotherapists three times a day, either IET + AC (intervention group, n=246) or nasal suction (NS, control group, n=250). Only physiotherapists were aware of the allocation group of the infant. The primary outcome was time to recovery, defined as 8 hours without oxygen supplementation associated with minimal or no chest recession, and ingesting more than two-thirds of daily food requirements. Secondary outcomes were intensive care unit admissions, artificial ventilation, antibiotic treatment, description of side effects during procedures, and parental perception of comfort. Statistical analysis was performed on an intent-to-treat basis. Median time to recovery was 2.31 days, (95% confidence interval [CI] 1.97-2.73) for the control group and 2.02 days (95% CI 1.96-2.34) for the intervention group, indicating no significant effect of physiotherapy (hazard ratio [HR]=1.09, 95% CI 0.91-1.31, p=0.33). No treatment by age interaction was found (p=0.97). Frequency of vomiting and transient respiratory destabilization was higher in the IET + AC group during the procedure (relative risk [RR]=10.2, 95% CI 1.3-78.8, p=0.005 and RR=5.4, 95% CI 1.6-18.4, p=0.002, respectively). No difference between groups in bradycardia with or without desaturation (RR=1.0, 95% CI 0.2-5.0, p=1.00 and RR=3.6, 95% CI 0.7-16.9, p=0.10, respectively) was found during the procedure. Parents reported that the procedure was more arduous in the group treated with IET (mean difference=0.88, 95% CI 0.33-1.44, p=0.002), whereas there was no difference regarding the assessment of the child's comfort between both groups (mean difference=-0.07, 95% CI -0.53 to 0.38, p=0.40). No evidence of differences between groups in intensive care admission (RR=0.7, 95% CI 0.3-1.8, p=0.62), ventilatory support (RR=2.5, 95% CI 0.5-13.0, p=0.29), and antibiotic treatment (RR=1.0, 95% CI 0.7-1.3, p=1.00) was observed. IET + AC had no significant effect on time to recovery in this group of hospitalized infants with bronchiolitis. Additional studies are required to explore the effect of chest physiotherapy on ambulatory populations and for infants without a history of atopy. ClinicalTrials.gov NCT00125450.

Study objectives To present diagnosis and treatment modalities of children with interstitial lung disease associated with frequent or rare surfactant protein C gene (SFTPC) mutation. Patients Twenty-two children with chronic lung disease associated with SFTPC mutation in a heterozygous form. Results Mutations located in the BRICHOS domain (‘BRICHOS domain’ group) were identified in six children, whereas 16 children carried mutations located outside the BRICHOS domain (‘non-BRICHOS domain’ group). The median age of onset was 3 (0–24) months. Four patients had neonatal respiratory distress, and symptom onset was associated with acute bronchiolitis in nine patients. Cough, tachypnoea and failure to thrive were initially noticed in all the children. Physical examination at presentation revealed tachypnoea (n=22), clubbing (n=1) and crackles (n=5). Low oxygen saturation (<95%) was observed in 18 patients. The predominant findings on initial high-resolution CT (HRCT) scans were basal-predominant ground-glass opacity (n=21) and cystic spaces (n=3). Bronchoalveolar lavage fluid (BALF) cell counts showed 379±56×103 cells/ml with increased neutrophil percentage (18±4%) independent of the mutation status. The median follow-up was 3.2 (1–18.3) years. Eighteen patients were treated by monthly methylprednisolone pulses associated with oral prednisolone (n=16), hydroxychloroquine (n=11) and/or azithromycin (n=4). Fifteen patients benefited from enteral nutrition. Conclusion Initial diagnosis is based on clinical presentation, radiological features and BALF analysis, but the definitive diagnosis requires genetic analysis. Although progressive improvement was seen in most patients, the development of new therapeutic strategies with minimal side effects is needed.

Various pulmonary phenotypes have been described, including RDS in term infants, ILD in children, and more recently in adults Aim: To describe the pulmonary phenotypes in patients with NKX2-1 mutations, including the clinical and radiological features, course of treatment and outcome. Methods: We retrospectively studied the clinical presentation, treatment modalities and outcome in 16 patients with heterozygous NKX2-1 mutation associated with chronic lung disease.