Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance.

Primary ciliary dyskinesia (PCD) is a genetic disorder in which impaired ciliary function leads to chronic airway disease. Exome sequencing of a PCD subject identified an apparent homozygous frameshift variant, c.887_890delTAAG (p.Val296Glyfs∗13), in exon 5; this frameshift introduces a stop codon in amino acid 308 of the growth arrest-specific protein 2-like 2 (GAS2L2). Further genetic screening of unrelated PCD subjects identified a second proband with a compound heterozygous variant carrying the identical frameshift variant and a large deletion (c.867_∗343+1207del; p.?) starting in exon 5. Both individuals had clinical features of PCD but normal ciliary axoneme structure. In this research, using human nasal cells, mouse models, and X.laevis embryos, we show that GAS2L2 is abundant at the apical surface of ciliated cells, where it localizes with basal bodies, basal feet, rootlets, and actin filaments. Cultured GAS2L2-deficient nasal epithelial cells from one of the affected individuals showed defects in ciliary orientation and had an asynchronous and hyperkinetic (GAS2L2-deficient = 19.8 Hz versus control = 15.8 Hz) ciliary-beat pattern. These results were recapitulated in Gas2l2-/- mouse tracheal epithelial cell (mTEC) cultures and in X. laevis embryos treated with Gas2l2 morpholinos. In mice, the absence of Gas2l2 caused neonatal death, and the conditional deletion of Gas2l2 impaired mucociliary clearance (MCC) and led to mucus accumulation. These results show that a pathogenic variant in GAS2L2 causes a genetic defect in ciliary orientation and impairs MCC and results in PCD.

Cross-sectional assessment of exertional dyspnea in otherwise healthy children.

OBJECTIVES: Exertional dyspnea during sport at school in children with asthma or in otherwise healthy children is commonly attributed to exercise-induced asthma (EIA), but when a short-acting beta agonist (SABA) trial fails to improve symptoms the physician is often at a loose end. DESIGN: The aims were to prospectively assess the causes of exertional dyspnea in children/adolescents with or without asthma using a cardiopulmonary exercise test while receiving a SABA and to assess the effects of standardized breathing/reassurance therapy. RESULTS: Seventy-nine patients (12.2 ± 2.3 years, 41 girls, 49 with previously diagnosed asthma) with dyspnea unresponsive to SABA were prospectively included. Exercise test outcomes depicted normal or subnormal performance with normal ventilatory demand and capacity in 53/79 children (67%) defining a physiological response. The remaining 26 children had altered capacity (resistant EIA [n = 17, 9 with previous asthma diagnosis], vocal cord dysfunction [n = 2]) and/or increased demand (alveolar hyperventilation [n = 3], poor conditioning [n = 7]). Forty-two children who had similar characteristics than the remaining 37 children underwent the two sessions of standardized reassurance therapy. They all demonstrated an improvement that was rated "large." The degree of improvement correlated with % predicted peak V'O2 (r = -0.37, P = 0.015) and peak oxygen pulse (r = -0.45, P = 0.003), whatever the underlying dyspnea cause. It suggested a higher benefit in those with poorer conditioning condition. CONCLUSIONS: The most frequent finding in children/adolescents with mild exertional dyspnea unresponsive to preventive SABA is a physiological response to exercise, and standardized reassurance afforded early clinical improvement, irrespective of the dyspnea cause.

Influenza-like illness responsible for severe exacerbations in asthmatic children during H1N1 pandemic: a survey before vaccination.

BACKGROUND: Asthma seems to be the more prevalent underlying condition in patients hospitalized for H1N1-related flu. METHODS: A prospective survey was conducted during the early phase of H1N1 pandemic in France in asthmatic children before vaccination to assess whether severe exacerbations in childhood asthma are associated with influenza-like illness (ILI, the definition of H1N1-related flu in a pandemic). Eight pediatricians in primary care distributed in three localities (Paris, south suburb, and west suburb) conducted the survey (4 weeks/locality from week 36 to 47). At each visit, the pediatrician filled a questionnaire entering the information regarding asthma treatment, severe exacerbation (at least 3 days' use of systemic corticosteroids), and ILI (temperature ≥37.8°C, cough, and/or sore throat, in the absence of a known cause other than influenza) during the past 3 weeks. RESULTS: The survey included 1155 asthmatic children (mean age [SD]: 7.5 years [4.1]); almost all visits were scheduled (99%). A severe exacerbation was recorded in 121 children [10.5%; 95% confidence interval (CI): 8.7-12.2%], which was concomitant with ILI in 20 children (16.5%; 95% CI: 9.9-23.2%), whereas 1034 children did not exhibit any exacerbation. In these latter children, 40 ILI were observed (3.9%; 95% CI: 2.7-5.0%), which constituted a significantly lesser percentage as compared with children with both exacerbation and ILI (p < .0001). This result remained significant in each locality. Overall, 60/1155 (5.2%; 95% CI: 3.9-6.5%) asthmatic children had an ILI. CONCLUSIONS: Our survey shows that severe exacerbation and ILI are strongly associated during the H1N1 pandemic in asthmatic children.

Impact of consensus development conference guidelines on primary care of bronchiolitis: are national guidelines being followed?

AIM: To measure the impact of French national consensus guidelines on the clinical practices of primary care paediatricians and general practitioners. DESIGN: Non-randomized intervention study, with a first survey 1 year before the consensus development conference and a second survey 1 year after. INTERVENTION: Implementation of bronchiolitis management guidelines through the medical press and the Internet. SUBJECTS: Paediatricians and general practitioners treating infants 1 year of age and under consulting for a first-time episode of bronchiolitis. RESULTS: Ninety-three doctors and 510 infants were included during the first phase of the study and 96 doctors and 394 infants during the second phase. This study showed a slight increase in adherence to the guidelines for non-validated drugs (6.6% adherence before and 14.3% after), general advice (29.0% adherence before and 57.1% after) and flow modulation respiratory physical therapy (91.9% adherence before and 98.8% after). Increase in adherence to guidelines for other practices, that is, hospitalization, prescribing antibiotics and complementary examinations, was not statistically significant. Adherence to the guidelines on providing general advice increased the most between the two studies. CONCLUSION: The guidelines helped practitioners evolve slightly in their approach to the treatment of bronchiolitis. Non-validated drugs remain frequently used. Additional resources for implementing the guidelines should be provided to improve primary care doctors' practices.