Primary ciliary dyskinesia (PCD) is an orphan disease (MIM 244400), autosomal recessive inherited, characterized by motile ciliary dysfunction. The estimated prevalence of PCD is 1:10,000 to 1:20,000 live-born children, but true prevalence could be even higher. PCD is characterized by chronic upper and lower respiratory tract disease, infertility/ectopic pregnancy, and situs anomalies, that occur in ≈50% of PCD patients (Kartagener syndrome), and these may be associated with congenital heart abnormalities. Most patients report a daily year-round wet cough or nose congestion starting in the first year of life. Daily wet cough, associated with recurrent infections exacerbations, results in the development of chronic suppurative lung disease, with localized-to-diffuse bronchiectasis. No diagnostic test is perfect for confirming PCD. Diagnosis can be challenging and relies on a combination of clinical data, nasal nitric oxide levels plus cilia ultrastructure and function analysis. Adjunctive tests include genetic analysis and repeated tests in ciliary culture specimens. There are currently 33 known genes associated with PCD and correlations between genotype and ultrastructural defects have been increasingly demonstrated. Comprehensive genetic testing may hopefully screen young infants before symptoms occur, thus improving survival. Recent surprising advances in PCD genetic designed a novel approach called “gene editing” to restore gene function and normalize ciliary motility, opening up new avenues for treating PCD. Currently, there are no data from randomized clinical trials to support any specific treatment, thus, management strategies are usually extrapolated from cystic fibrosis. The goal of treatment is to prevent exacerbations, slowing the progression of lung disease. The therapeutic mainstay includes airway clearance maneuvers mainly with nebulized hypertonic saline and chest physiotherapy, and prompt and aggressive administration of antibiotics. Standardized care at specialized centers using a multidisciplinary approach that imposes surveillance of lung function and of airway biofilm composition likely improves patients’ outcome. Pediatricians, neonatologists, pulmonologists, and ENT surgeons should maintain high awareness of PCD and refer patients to the specialized center before sustained irreversible lung damage develops. The recent creation of a network of PCD clinical centers, focusing on improving diagnosis and treatment, will hopefully help to improve care and knowledge of PCD patients.

Primary ciliary dyskinesia (PCD) is a recessively inherited disease that leads to chronic respiratory disorders owing to impaired mucociliary clearance. Conventional transmission electron microscopy (TEM) is a diagnostic standard to identify ultrastructural defects in respiratory cilia but is not useful in approximately 30% of PCD cases, which have normal ciliary ultrastructure. DNAH11 mutations are a common cause of PCD with normal ciliary ultrastructure and hyperkinetic ciliary beating, but its pathophysiology remains poorly understood. We therefore characterized DNAH11 in human respiratory cilia by immunofluorescence microscopy (IFM) in the context of PCD. We used whole-exome and targeted next-generation sequence analysis as well as Sanger sequencing to identify and confirm eight novel loss-offunction DNAH11 mutations. We designed and validated a monoclonal antibody specific to DNAH11 and performed highresolution IFM of both control and PCD-affected human respiratory cells, as well as samples from green fluorescent protein (GFP)-leftright dynein mice, to determine the ciliary localization of DNAH11. IFM analysis demonstrated native DNAH11 localization in only the proximal region of wild-type human respiratory cilia and loss of DNAH11 in individuals with PCD with certain loss-of-function DNAH11 mutations. GFP-left-right dynein mice confirmed proximal DNAH11 localization in tracheal cilia. DNAH11 retained proximal localization in respiratory cilia of individuals with PCD with distinct ultrastructural defects, such as the absence of outer dynein arms (ODAs). TEM tomography detected a partial reduction of ODAs in DNAH11-deficient cilia. DNAH11 mutations result in a subtle ODA defect in only the proximal region of respiratory cilia, which is detectable by IFM and TEM tomography.Keywords: left-right dynein; primary ciliary dyskinesia; normal ciliary ultrastructure; immunofluorescence microscopy; transmission electron microscopy Clinical RelevanceConventional transmission electron microscopy (TEM) is not diagnostic for approximately 30% of primary ciliary dyskinesia (PCD) cases because they have normal ciliary ultrastructure; DNAH11 mutations are a common cause of PCD with normal ciliary ultrastructure and hyperkinetic ciliary beating, but its molecular characterization in human respiratory cilia is completely lacking. We show that DNAH11 distinctly localizes to the proximal region of respiratory cilia, independently of all previously described factors governing dynein arm assembly. TEM tomography detects a partial reduction of outer dynein arms in only the proximal region of DNAH11-deficient cilia. This helps explain why DNAH11 mutations result in normal ciliary ultrastructure and hyperkinetic ciliary beating and suggests a novel mode of axonemal assembly in respiratory cilia.

Childhood asthma remains a multifactorial disease with heterogeneous clinical phenotype and complex genetic inheritance. The primary aim of asthma management is to achieve control of symptoms, in order to reduce the risk of future exacerbations and progressive loss of lung function, which results especially challenging in patients with difficult asthma. When asthma does not respond to maintenance treatment, firstly, the correct diagnosis needs to be confirmed and other diagnosis, such as cystic fibrosis, primary ciliary dyskinesia, immunodeficiency conditions or airway and vascular malformations need to be excluded. If control remains poor after diagnostic confirmation, detailed assessments of the reasons for asthma being difficult-to-control are needed. Moreover, all possible risk factors or comorbidities (gastroesophageal reflux, rhinosinusitis, dysfunctional breathing and/or vocal cord dysfunction, obstructive sleep apnea and obesity) should be investigated. At the same time, the possible reasons for poor symptom control need to be find in all modifiable factors which need to be carefully assessed. Non-adherence to medication or inadequate inhalation technique, persistent environmental exposures and psychosocial factors are, currently, recognized as the more common modifiable factors. Based on these premises, investigation and management of asthma require specialist multidisciplinary expertise and a systematic approach to characterizing patients' asthma phenotypes and delivering individualized care. Moreover, since early wheezers are at higher risk of developing asthma, we speculate that precocious interventions aimed at early diagnosis and prevention of modifiable factors might affect the age at onset of wheezing, reduce the prevalence of persistent later asthma and determine long term benefits for lung health.

Chest MRI was equivalent to HRCT to determine the extent of lung disease in children with non-CF lung disease. The findings support the use of chest MRI as an alternative to HRCT in diagnostic pathways for paediatric chronic lung disorders.

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Growing evidence indicates that inherited metabolic diseases are increasingly being recognised. Life expectancy for many patients is progressively improving because new therapeutic strategies are available. Because most inherited metabolic diseases are systemic disorders, virtually all organs may be involved. Respiratory disease complicates the management of several inherited metabolic diseases, either at presentation or as late-onset features. This review will describe the most exemplary respiratory manifestations of inherited metabolic diseases in childhood and adulthood. Since airways disease worsens the morbidity of many inherited metabolic disorders, leading to increased hospitalisations, mortality and overall healthcare costs, respiratory manifestations of inherited metabolic diseases need to be carefully recognised and treated. All patients with inherited metabolic disease and suspected airway disease should undergo a detailed diagnostic work-up. Current treatments for several inherited metabolic diseases (including enzyme replacement therapy, substrate reduction, bone marrow transplantation, or even more innovative strategies such as pharmacological chaperone or gene therapies) may provide significant benefits for associated respiratory disease. The integration of several specialists dedicated to airway disease management in a multidisciplinary team is essential to provide the most appropriate care to children and adults with inherited metabolic disease. @ERSpublications Proper management of respiratory disease is mandatory for reducing morbidity and mortality of inherited metabolic disease

Assessment of resting pulmonary function and cardiopulmonary functional capacity could contribute to the evaluation of pulmonary impairment in PCD. Given the benefit of physical exercise on airway clearance and on general health and quality of life, patients with PCD should be encouraged to adopt an active lifestyle.

In the past decades improved surgical techniques and better neonatal supportive care have resulted in reduced mortality of patients with esophageal atresia (EA), with or without tracheoesophageal fistula, and in increased prevalence of long-term complications, especially respiratory manifestations. This integrative review describes the techniques currently used in the pediatric clinical practice for assessing EA-related respiratory disease. We also present a novel algorithm for the evaluation and surveillance of lung disease in EA. A total of 2813 articles were identified, of which 1451 duplicates were removed, and 1330 were excluded based on review of titles and abstracts. A total of 32 articles were assessed for eligibility. Six reviews were excluded, and 26 original studies were assessed. Lower respiratory tract infection seems frequent, especially in the first years of life. Chronic asthma, productive cough, and recurrent bronchitis are the most common respiratory complaints. Restrictive lung disease is generally reported to prevail over the obstructive or mixed patterns, and, overall, bronchial hyperresponsiveness can affect up to 78% of patients. At lung imaging, few studies detected bronchiectasis and irregular cross-sectional shape of the trachea, whereas diffuse bronchial thickening, consolidations, and pleural abnormalities were the main chest X-ray findings. Airway endoscopy is seldom included in the available studies, with tracheomalacia and tracheobronchial inflammation being described in a variable proportion of cases. A complete diagnostic approach to long-term respiratory complications after EA is mandatory. In the presence of moderate-to-severe airway disease, patients should undergo regular tertiary care follow-up with functional assessment and advanced chest imaging.