Rola Abou Taam

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.

Characteristics of disorders associated with genetic mutations of surfactant protein C

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.

Add-on omalizumab in children with severe allergic asthma: a 1-year real life survey

Omalizumab has been shown to reduce exacerbation rates in moderate to severe allergic asthma. Our aim was to evaluate omalizumab efficacy and safety in a real-life setting in severe asthmatic children. 104 children (aged 6–18 years), followed up in paediatric pulmonary tertiary care centres, were included at the beginning of omalizumab treatment. Asthma control levels, exacerbations, inhaled corticosteroid dose, lung function and adverse events were evaluated over 1 year. Children were characterised by allergic sensitisation to three or more allergens (66%), high IgE levels (mean 1125 kU·L−1), high rate of exacerbations (4.4 per year) and healthcare use during the previous year, and high inhaled corticosteroid dose (mean 703 &mgr;g equivalent fluticasone per day). Asthma control levels defined as good, partial or poor, improved from 0%, 18% and 82% at entry to 53%, 30% and 17% at week 20, and to 67%, 25% and 8% at week 52, respectively (p<0.0001). Exacerbation and hospitalisation rates dropped by 72% and 88.5%, respectively. At 12 months, forced expiratory volume in 1 s improved by 4.9% (p=0.023), and inhaled corticosteroid dose decreased by 30% (p<0.001). Six patients stopped omalizumab for related significant adverse events. Omalizumab improved asthma control in children with severe allergic asthma and was generally well tolerated. The observed benefit was greater than that reported in clinical trials. Omalizumab improves asthma control in children with severe allergic asthma and is generally well tolerated http://ow.ly/oLoBp

Familial interstitial disease with I73T mutation: A mid‐ and long‐term study

To describe the long‐term course and the management in children of chronic interstitial lung disease associated with I73T mutation.

Real-life long-term omalizumab therapy in children with severe allergic asthma

We previously reported the French real-life experience of 1 year of add-on treatment with omalizumab in 101 severe allergic asthmatic children (6–18 years), 92 of whom were still receiving the treatment at the end of the first year [1]. The study provided complementary data to the previous randomised trials [2–6]. We showed a marked drop of 72% in the mean rate of severe exacerbations (from 4.4 per patient during the preceding year to 1.25 during the year of treatment) and of 88.5% for hospitalisations (44% of the patients during the preceding year to 6.7% during the year of treatment); a large improvement in asthma control (from 0% at initiation to 67% of well-controlled patients after 1 year); a decrease of 30% of the mean inhaled corticosteroid (ICS) dose (from 703 at initiation to 488 µg fluticasone equivalent per day after 1 year); and a forced expiratory volume in 1 s (FEV1) increase, from a mean of 88% to 92.1% of the predicted value. Treatment was discontinued in six patients due to serious adverse events attributed to omalizumab by the practitioner. Here we report the outcome of this cohort after 2 years of omalizumab treatment. Beneficial effects at 2 years of omalizumab on severe exacerbations and control in severe allergic asthmatic children http://ow.ly/LGgnw

Characterization of SLC26A9 in patients with CF-like lung disease.

Diffuse bronchiectasis is a common problem in respiratory clinics. We hypothesized that mutations in the solute carrier 26A9 (SLC26A9) gene, encoding for a chloride (Cl−) transporter mainly expressed in lungs, may lead to defects in mucociliary clearance. We describe two missense variants in the SLC26A9 gene in heterozygote patients presenting with diffuse idiopathic bronchiectasis : p.Arg575Trp, identified in a patient also heterozygote for p.Phe508del in the CFTR gene; and p.Val486Ile. Expression of both mutants in Xenopus laevis oocytes abolished SLC26A9‐mediated Cl− conductance without decreasing protein membrane expression. Coexpression of CFTR with SLC26A9–p.Val486Ile resulted in a significant increase in the Cl− current induced by PKA stimulation, similar to that obtained in oocytes expressing CFTR and SLC26A9–WT. In contrast, coexpression of CFTR with SLC26A9–p.Arg575Trp inhibited SLC26A9‐enhanced CFTR activation upon PKA. Further structure–function analyses led us to propose a site encompassing Arg575 in the SLC26A9–STAS domain for CFTR–SLC26A9 interaction. We hypothesize that SLC26A9–p.Arg575Trp prevented SLC26A9‐mediated functional activation of CFTR by altering SLC26A9–CFTR interaction. Although we cannot confirm that these mutations by themselves are deleterious, we propose that they trigger the pathogenic role of a single CFTR mutation and provide insight into a novel mechanism of Cl− transport alteration across the respiratory mucosa, based on functional inhibition of CFTR.

Circulating IL-17-producing mucosal-associated invariant T cells (MAIT) are associated with symptoms in children with asthma

IL-17 and mucosal-associated invariant T (MAIT) cells have been involved in asthma pathogenesis. However, IL-17-producing MAIT cells (MAIT-17) were not evidenced. We aimed to determine whether circulating MAIT-17 were detectable in children with asthma, and whether they correlated with asthma symptoms or lung function. Children from the SPASM cohort of preschoolers with severe wheeze were reassessed for asthma at school age, and categorized as exacerbators (1 or more severe exacerbations in the previous 12months) or non-exacerbators. Nineteen children (10.9years) were included (9 non-exacerbators, 10 exacerbators). Circulating MAIT-17 were detected by flow cytometry. Their frequency was higher in exacerbators than in non-exacerbators (1.9 [1.01-3.55] vs 0.58 [0.46-1.15], p<0.01). MAIT-17 correlated with the number of severe exacerbations (r=0.68, p<0.001), and correlated negatively with the ACT score (r=-0.55, p=0.01). In summary, MAIT-17 are present in children with asthma and associated with asthma symptoms.

Presence of tracheal bronchus in children undergoing flexible bronchoscopy.

BACKGROUND AND OBJECTIVES Tracheal bronchus (TB) is a rare congenital malformation of the lung tree with a bronchus originating from the trachea. Only a small number of publications have analyzed the frequency and diagnostic procedure of TB in children, based on a restricted sample of patients. In the present study, we analyze and discuss new aspects of prevalence, clinical presentation and associated malformations of TB based on a large pediatric cohort. METHODS Data from 5970 children having a flexible bronchoscopy for investigation of respiratory symptoms were selected. We analyzed the anaesthesic management, the presence of associated malformations, and all tracheobronchial anomalies observed during the endoscopic procedure. RESULTS Fifty-seven cases of tracheal bronchus were identified (0.9%). In the majority of them, tracheal bronchus was a fortuitous discovery without clear clinical relevance. Statistical analysis revealed that the majority of TB originated from the middle and lower one third of the trachea (56%). 61.5% of patients had associated anomalies such as syndromic association (21%), cardiac malformations (19.2%) or tracheal stenosis (14%). Only 38.5% of children had no associated anomalies. CONCLUSIONS Tracheal bronchus is a rare morphological anomaly of the tracheobronchial tree. Most often TB is associated with other birth defects such as another tracheo-bronchial tree malformation, vascular abnormality, congenital heart malformation or in the context of a syndromic pattern. A relationship between respiratory symptoms and the presence of TB is very rare and selective treatment is infrequent.

Diffuse Lymphoplasmacytic Bronchiolitis in Cartilage-Hair Hypoplasia

Three children with cartilage-hair hypoplasia presented with chronic obstructive symptoms and bronchiolar wall thickening on high-resolution computed tomography scanning. In all children, surgical lung biopsy demonstrated diffuse dilated lymphoplasmacytic bronchiolitis. The bronchiolar wall was infiltrated by a lymphocyte sheath with plasma cell differentiation and dispersed secondary follicles. Clarithromycin substantially improved respiratory symptoms and pulmonary function, allowing children to return home.

Drug-induced hallucination: a case/non case study in the French Pharmacovigilance Database

Background and Objectives: Hallucinations are sensory perceptions which occur without external stimuli. There are associated with psychiatric disease but also can be related to organic disease and drug or toxic exposure. The purpose of our study was to inves- tigate the association between exposure to medications and the reporting of hallucinations using data from the spontaneous-reporting French Pharmacovigilance Database (FPVD). Methods: We used the case/noncase method in the FPVD. Cases were all the observa- tions of hallucination with the LLT term “perception disturbances”, registered into the FPVD from January 1985 to Jan 2013. Data were expressed as odds ratio (OR) with their 95% confidence intervals. Results : Among the 469,181 reports of adverse effects recorded between 1985 and 2013, 4,086 are hallucinations. For about 50% of these hallucinations were experimented by patient older than 65 years old. A statistically significant OR was found with several medications included rasagiline (OR 17.6 [95%CI 10.4-29.8]), zolpidem (OR 12.9 [95%CI 11.3-14.8]), methylphenidate (OR 9.3 [95%CI 5.9-14.6]) and baclofene (OR 5.4 [95%CI 3.7-7.8]). An increased risk of hallucinations was also observed with non central nervous system drugs, including er- tapenem (OR 24.0 [95%CI 14.2-40.5]), voriconazole (OR 12.9[95%CI 10.2-16.5]) and valacyclovir (OR 9.1 [95%CI 6.9-11. 9]). Conclusions: This pharmacoepidemiological study describes an association between drugs and hallucinations. This relationship involves not only some already suspected drugs but also other drugs less known to induce such an adverse reaction. Despite the mandatory limits of this kind of study, these data should lead to special precautions in patient at risk